Next Article in Journal
Oxidative Stress and Antioxidants in Neurodegenerative Disorders
Next Article in Special Issue
Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review
Previous Article in Journal
Characterization of Maternal Circulating MicroRNAs in Obese Pregnancies and Gestational Diabetes Mellitus
Previous Article in Special Issue
Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress-Related Liver Diseases
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines

Internal Medicine Department, Zaporozhye Medical Academy of Postgraduate Education, 69000 Zaporozhye, Ukraine
Klinik Barmelweid, Department of Psychosomatic Medicine and Psychotherapy, 5017 Barmelweid, Switzerland
Department of Internal Medicine & Nephrology, VitaCenter, 69000 Zaporozhye, Ukraine
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Internal Medicine Department, Zaporozhye State Medical University, 69035 Zaporozhye, Ukraine
Author to whom correspondence should be addressed.
Antioxidants 2023, 12(2), 516;
Received: 16 January 2023 / Revised: 12 February 2023 / Accepted: 16 February 2023 / Published: 17 February 2023


Cardiac hepatopathy refers to acute or chronic liver damage caused by cardiac dysfunction in the absence of any other possible causative reasons of liver injury. There is a large number of evidence of the fact that cardiac hepatopathy is associated with poor clinical outcomes in patients with acute or actually decompensated heart failure (HF). However, the currently dominated pathophysiological background does not explain a role of metabolic regulative proteins secreted by hepatocytes in progression of HF, including adverse cardiac remodeling, kidney injury, skeletal muscle dysfunction, osteopenia, sarcopenia and cardiac cachexia. The aim of this narrative review was to accumulate knowledge of hepatokines (adropin; fetuin-A, selenoprotein P, fibroblast growth factor-21, and alpha-1-microglobulin) as adaptive regulators of metabolic homeostasis in patients with HF. It is suggested that hepatokines play a crucial, causative role in inter-organ interactions and mediate tissue protective effects counteracting oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and necrosis. The discriminative potencies of hepatokines for HF and damage of target organs in patients with known HF is under on-going scientific discussion and requires more investigations in the future.

1. Introduction

The number of new cases of heart failure (HF) is steadily increasing worldwide. The prevalence of HF with preserved ejection fraction (HFpEF) is currently higher than that of HF with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction [1,2,3]. The exact absolute risks for HF progression from stage A to stage C have remained stable over the past decade (8.4 per 100 person-years), regardless of the implementation of conventional strategies [4]. Previous observational studies found that one-year mortality in HF varied widely from 4% to 45% depending on the presence of acute or chronic HF, HF phenotype, age, gender and concomitant diseases [4,5,6]. According to the Acute Heart Failure Database (AHEAD) registry, liver function test abnormalities (elevations in total bilirubin, γ-glutamyltransferase, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase) were found in 76% of patients with known acute HF [7]. The PROTECT trial (Placebo-controlled Randomized study of the selective A1 adenosine receptor antagonist KW-3902 for patients hospitalized with acute HF and volume Overload to assess Treatment Effect on Congestion and renal funcTion) and the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) showed that acute HF including cardiogenic shock was a meaningful cause of cardiac liver dysfunction [8,9]. Moreover, patients with acute or actually decompensated HF were significantly more likely to have abnormalities in liver test than patients with chronic HF [9]. On the other hand, new-onset liver injury due to cardiac dysfunction has been shown to be a strong predictor for HF progression, higher risks of hospitalization and poor clinical outcomes (all-cause mortality and cardiovascular death) and quality of life [9,10,11]. Along with it, there is evidence of the fact that a severity of liver injury secondary to progressive HF was loosely associated with adverse cardiac remodeling, skeletal muscle dysfunction and sarcopenia/cardiac cachexia [12,13].
However, in HF, multiple pathophysiological interactions between neurohumoral and systemic/local inflammatory activations, as well as an altered immune response, lead not only to adverse cardiac remodeling but also to worsening hepatic circulation and sequelae following the development of acute cardiogenic liver injury and congestive hepatopathy [14,15,16]. The pathogenesis of cardiac hepatopathy is complex and involves underlying canonical molecular mechanisms that overlap with the development and progression of HF (i.e., centrilubular liver necrosis, dilated sinusoids and perisinusoidal fibrosis due to hypoperfusion associated with fluid retention and passive congestion, altered electrolyte and protein metabolism, iron homeostasis and secondary portal hypertension). Additionally, other pathophysiological pathways link liver dysfunction to renal dysfunction, altered endothelial function, anabolic/catabolic imbalance, abnormalities in the intestinal microbiome, impaired metabolism of adipose tissue and skeletal muscle [17,18,19]. Less is known about the role of hepatokines (adropin, fetuin-A, selenoprotein P, alpha-1-microglobulin) produced by hepatocytes as a result of oxidative stress and microvascular inflammation in progressive dysfunction of other organs in HF, including adverse cardiac remodeling, renal damage, adipose tissue inflammation and skeletal muscle myopathy [20]. The majority of hepatokines are synthesized and released mainly by hepatocytes (adropin, fibroblast growth factor-21 [FGF-21], alpha-1-microglobulin), whereas others (fetuin-A and fetuin-B) are additionally produced by various tissues including adipose tissues. They exerted their modality to regulate liver metabolism and energy homeostasis, local synthesis and releasing inflammatory cytokines, activation of stellate cells and fibroblasts, local antigen-presenting cells, and provided immune adaptive, anti-inflammatory, anti-oxidative, anti-apoptotic and protective effects with remote organs (heart, lung, kidney, pancreas) and tissues (vasculature, white adipose tissue, pericardial adipose tissue, skeletal muscles) [21]. Although all these processes are crucial for HF progression, because they affect target organ dysfunction, vascular integrity and tissue reparation, understanding underlying molecular mechanisms in connection with their regulation by hepatokines retains uncertain. On the other hand, it remains unclear whether hepatokines cause the direct and initial attack on the heart inducing cardiac remodeling through activating Akt, nuclear factor-κB (NF-κB), and ERK signaling and/or chances to get damaged due to other organs damage-associated chemical mediators like acute renal failure and skeletal muscle dysfunction or, in contrast, their act as adaptive modulator of endogenous repair system [22]. The aim of this study was to increase the knowledge of hepatokines as adaptive regulators of metabolic homeostasis in patients with HF.

2. Definition, Morphological Criteria, and Biochemical Profiling of Liver Damage in HF

The current paradigm of cardiac hepatopathy refers to any hepatocyte injury caused by acute or chronic cardiac dysfunction in the absence of clear evidence of other possible causes of liver injury [21,22]. Although there is no consensus on the definition and terminology of cardiac hepatopathy, the majority of experts use the terms congestive cardiac hepatopathy (CCH) and acute cardiogenic liver injury (ACLI) to describe two different aspects of the disease [23,24,25,26]. CCH is the most common disease in HF caused by passive venous congestion of the liver. Several chronic cardiac diseases, such as constrictive pericarditis, tricuspid regurgitation, primary and secondary cardiomyopathies, inherited cardiac defects and cardiac hypertrophy, associated with chronic HF, usually lead to congestion and thus to the development of CCH [27,28]. There is ample clinical evidence that CCH is closely related to HFrEF/HFmrEF and corresponds to the New York Heart Association (NYHA) HF functional class [29]. In contrast, ACLI is most commonly associated with arterial hypoperfusion and downstream hypoxia due to acute HF resulting from acute myocardial infarction, acute decompensated chronic HF, progressive natural history of severe myocarditis and cardiomyopathies [30]. Nevertheless, the role of primary hypotension in the development of ACLI is controversial. For example, a retrospective analysis of a cohort of 31 HF patients with clinical and biochemical evidence of ACLI revealed that hypotension alone cannot be considered as a trigger of acute liver injury [31]. Rather, other factors such as multiple concomitant diseases in collaboration with various epigenetic influences are implicated for the occurrence of ACLI [32].
Histologically, these two phenotypes of cardiac hepatopathy appear sufficiently distinct. In most cases, CCH is characterized by sinusoidal dilatation associated with extravasation of red blood cells from sinusoids into periportal areas and replacement of hepatocytes by red blood cells, as well as the expression of necrotic areas without severe cellular infiltration and apoptosis of cells in the third zone of Rappaport acini [21,33]. To note, there is evidence of the fact that the small diameter of fenestrae in sinusoids in humans is likely to be a serious obstacle for hepatocyte transduction, so that higher variability of clinical presentation of CCH due to passive congestion may relate to genetic reasons [33]. The extension of periportal necrotic zones together with secondary centrilobular necrosis and accumulation of fibrosis tissue may eventually lead to ineffective intrahepatic circulation supporting ischemia/hypoxia and loss of functional hepatocytes, endothelialization of sinusoids and development of liver cirrhosis in advanced cases [21,34]. The main histological findings in ACLI are massive necrosis of the third zone of Rappaport acini, gross deformation of the liver parenchyma, large fibrotic areas along with rapidly progressive portal hypertension and splenic hypertrophy, often leading to the early onset of hepato-renal syndrome [21,35].
In this context, the primary laboratory findings of cardiac hepatopathy vary depending on numerous factors that include not only the phenotype of the disease, but also the duration of hypotension, the type of cardiac dysfunction (left-sided, right-sided, or biventricular), the presence of comorbidities, patient age and gender [36,37]. Indeed, the greatest increase in transaminases was observed in patients with right-sided or biventricular HF than in left-sided HF [37]. Meanwhile, the prevalence of CCD in HF patients depended on a signature of comorbidity, male gender and older age [7,8,9]. Thus, cardiac hepatopathy may manifest as asymptomatic elevation of serum levels of aminotransferases and/or bilirubin and severe liver injury with significant elevation of aminotransferases, alkaline phosphatase, γ-glutamyltranspeptidase, lactate dehydrogenase and a decrease in plasma albumin levels. Clinical signs of cholestasis, ascites, peripheral edema, portal hypertension and concomitant oligoanuria may not be closely related to the phenotype of cardiac hepatopathy [38]. However, regardless of its phenotype, cardiac hepatopathy has strong prognostic value in identifying all-cause mortality, cardiovascular events and mortality associated with HF and has some particular implications for the management of patients undergoing cardiac assist device implantation or heart transplantation [39].

3. Common Underlying Molecular Mechanisms of Cardiac Hepatopathy

Figure 1 illustrates the main underlying molecular mechanisms of the development of both phenotypes of cardiac hepatopathy. Primary liver ischemia/reperfusion and/or passive liver congestion with secondary tissue ischemia/hypoxia together with oxidative stress are thought to trigger a secondary locally and systemically inflammatory cascade that induces microvascular impairment, intrahepatic thrombosis, liver necrosis/apoptosis, and development of liver fibrosis with its conversion to cirrhosis and interorgan interactions during HF pathogenesis. Along with it, there is assumption of a causative role of sinusoidal thrombi, which are direct reason for tissue ischemia and fibrosis. In addition, alterations in liver function lead to progressive changes in splanchnic blood flow, coronary circulation and systemic hemodynamics and thereby maintain liver fibrosis progression. Finally, cardiac hepatopathy is supported by inadequate secretion of various hepatokines, such as adropin, fetuin-A, FGF-21, alpha-1-microglobulin and selenoprotein P, which influence energy metabolism, local and systemic inflammation and immune response.

3.1. Ischemia/Reperfusion and Inflammation/Fibrosis Cascade

Ischemic injury of the liver is a component of ACLI induced by hypoxia due to hypoperfusion and is characterized by sequential damage to intracellular organelles and whole cells, cell swelling and further persistent disruption of Na+/K+-ATPase function [40,41]. The intracellular accumulation of low-oxidized lipids and proteins, overexpression of xanthine oxidase and NADPH oxidase leads to overproduction of reactive oxygen (ROS) and nitrogen species (such as peroxynitrite, hypochlorite), contributing to acidosis-induced suppression of mitochondrial transmembrane malate-aspartate exchange and carnitine-related mechanism of acyl-CoA transfer, and inducing ischemic mitochondrial dysfunction leading to alteration of mitochondrial permeability and ATP depletion [42]. In fact, the additional damage to liver tissue is a consequence of the paradoxically exacerbating restoration of perfusion by oxygen/Ca2+ delivery [43]. Finally, ROS, intracellular calcium overload, inflammatory cytokines (interleukin [IL]-1b, IL-2, tumor necrosis factor-alpha [TNF]) and chemokines (hypoxia-inducible factor-1α, C-X-C motif ligand-8, C-C motif ligand-2, C-C motif ligand-10) support the early activation of Kupffer cells, the late activation of polymorphic mononuclear cells and the accumulation of CD4+ T lymphocytes. Additionally, these processes activate stellate cells, mononuclear cells and platelets in perisinusoidal spaces and periportal areas and the post-ischemic disruption of liver microcirculation together with a decrease in sinusoidal density in liver parenchyma [44,45]. Antigen-presenting cells and CD4+ T lymphocytes secrete a variety of growth factors such as TNF-β, granulocyte-macrophage colony-stimulating factor and interferon gamma, which enable direct activation of Kupffer cells and promote their ability to synthesize and release inflammatory cytokines [46]. Meanwhile, in ACLI, nitric oxide levels were found to be sufficiently reduced [47]. Moreover, an imbalance between nitric oxide production by nitric oxide synthase and endothelin-1 leads to vasoconstriction of sinusoids and exacerbates the vicious cycle of altered blood circulation [48]. Overall, ischemic and post-ischemic oxidative stress and mitochondrial injury are considered potent triggers for further overexpression of inflammatory genes and activation of hepatocellular apoptosis, ferroptosis and necrosis during hepatic ischemia/reperfusion injury in acute HF [49]. Indeed, Tanaka et al. (2014) [49] found that numerous apoptotic hepatocytes in the third zone of Rappaport acinar were co-localized with NADPH oxidase 4 (NOX4) and that these findings were a consequence of hypoxia-induced intrahepatic microcirculatory failure but were not induced by activated APCs, such as macrophages and mononuclear cells. On the other hand, hepatocyte energy metabolism, as measured by determining the local activities of citrate synthase, carnitine palmitoyltransferase-1 and cytochrome c oxidase, was increased by inflammatory cytokines despite ultrastructural changes in mitochondria during hepatocyte apoptosis [50]. It is possible that the transmission of death signals in the early phase of hepatocyte apoptosis is mainly associated with the co-stimulation of APCs, while in the late phase it is regulated by other signals such as NOX4 and active caspase-3, Bax and Bcl-2 that might be regulated via Toll-like receptor-4 (TLR4)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3-beta (GSK-3β) signaling [51]. However, local production of inflammatory cytokines mediates expression of cell surface adhesion molecules (intracellular cell adhesion molecule, vascular cell adhesion molecule) on the surfaces of hepatocytes and endothelial cells, induces adherence of APCs and consequently leads to intravascular/intra-sinusoidal coagulation, which contributes to microcirculatory failure and autophagy [52,53]. Interestingly, ischemia/reperfusion-induced liver injury may be promoted by M1 polarization of macrophages via regulation of peroxisome proliferator-activated receptor-γ (PPAR-γ) in response to increasing anaerobic glycolysis and accumulation of lactic acid in the microenvironment [54]. Evidence suggests that polarization of hepatic M1 macrophages, which supports acute and chronic liver injury, can be promoted by gut-derived exosomes following intestinal ischemia/reperfusion [53,54]. Thus, decreased splanchnic blood flow is an independent factor contributing to liver injury. However, all these triggers prolong hepatic ischemia/hypoxia and exacerbate apoptosis/necrosis, creating a vicious cycle of excessive inflammatory response involving activated antigen presenting cells with excessive cytokine and ROS production, leading to further oxidative liver tissue damage [55,56].
The molecular pathways contributing to CCH are not different from those mentioned above, while ischemia is secondary to passive liver congestion and the reperfusion phase is closely related to decompensation of HF associated with unstable hemodynamics. Indeed, CCH is not as dramatic compared with ACLI, so the histological sequelae are not necessarily the same as those of ACLI. Initial dilatation of hepatic sinusoids due to passive liver congestion is associated with a degree of venous pressure in vena porta and results in the exudation of red blood cells, activated mononuclear cells, platelets and protein rich-fluid into the perisinusoidal space of Disse. However, low-grade inflammation and excessive fibrosis play a more significant role in the pathogenesis of CCH than in ACLI. There is strong evidence that inflammatory chemokine signaling (C-X-C motif ligand-8, C-C motif ligand-2, C-C motif ligand-10) derived from activated Kupffer cells induces polarization of monocyte-derived macrophages into the M1 phenotype and stimulates fibrogenesis through activation of hepatic stellate cells [57,58,59]. Another difference between CCH and ACLI concerns the advocacy of hepatic angiogenesis [60]. Indeed, hypoxia-induced vascular endothelial growth factor (VEGF) expression has been found to be crucial in advanced fibrosis, whereas inflammation in early stages of fibrotic transformation of the liver may involve VEGF in hepatic angiogenesis [60,61]. However, the low regenerative capacity of liver progenitor cells seems to be closely related to altered mitophagy, which is a selective form of autophagy for damaged and/or redundant mitochondria [62,63]. Indeed, pro-inflammatory cytokines such as TNF-alpha perform variable cellular responses, including cell proliferation, metabolic activation, inflammatory responses and apoptosis, acting through the PI3K/Akt pathway, transforming growth factor (TGF)-β signaling, Fas aggregation and NF-κB signaling [64,65,66]. There is strong evidence that TGF-β and pro-inflammatory cytokines synergistically promote collagen synthesis and support fibrosis via the pSmad3C pathway [66,67]. Last but not least, ferroptosis seems to be more sufficient than apoptosis for chronic ischemia-induced CCH [68]. Ferroptosis is triggered by nuclear factor E2-related factor 2, but not by hypoxia-inducible factor-1α, which is often considered to trigger apoptosis in ACLI [68,69]. In summary, CCH is considered to be a mild-to-moderate progressive disease that shows histological signs of progression from liver fibrosis to liver cirrhosis at the advanced stage of its natural evolution.

3.2. Intestinal Microbiota

Recent data show that the secretome of the gut microbiota may be involved in the regulation of liver regeneration after acute and chronic liver injury [70]. Therefore, different microbiota profiles were found to be associated with the rate of decompensation HF and thereby intervened in outcome in these patients [71]. Indeed, a wide range of secretory components, including gut-derived lipopolysaccharides, bile acids associated with gut microbiota and numerous bacterial metabolites (short-chain fatty acids and tryptophan metabolites), may influence protective capacity by protecting hepatocytes from injury and supporting repair [72]. Although there is no certain explanation for the transmission of signals from the microbiota to hepatocytes [73], the secretome of the intestinal microbiota is thought to mediate activities of the farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) axis and enhance the TGR5-glucagon-like peptide axis, which are involved in the metabolic regulation of proliferative response and attenuation of immunological imbalance [74,75]. In addition, lipopolysaccharide (LPS) derived from bacterial walls of the intestinal microbiota and bacterial DNAs, that are known TLR9 agonists, have been found at elevated levels in the peripheral blood of patients with various liver diseases [76,77]. Increased permeability of the intestinal vascular barrier to such macromolecules is the result of sufficient disruption of splanchnic blood flow, edema of the intestinal wall, free fluid in the peritoneum and maldigestion [78]. Finally, simultaneous stimulation of antigen-presenting cells by LPS and bacterial DNAs may lead to activation of the inducible form of nitric oxide synthase and release of nitric oxide, which is accompanied by systemic vasodilation and hyperdynamic changes in the circulation to prevent impaired perfusion of distant tissues [77,79,80]. Yet, several metabolites of the microbiota, such as trimethylamine N-oxide, tryptamine and indole-3-acetate, may attenuate inflammatory responses, insulin resistance, mitochondrial and endoplasmic reticulum dysfunction through binding with endoplasmic reticulum stress kinase PERK (EIF2AK3) and activation of transcription factor FoxO1, as well as they may mediate the expression of fatty acid synthase and sterol regulatory element-binding protein-1c in hepatocytes [81,82]. Normally, these metabolites reduced fatty-acid- and LPS-stimulated ability of macrophages to synthetize and release pro-inflammatory cytokines and inhibited the migration activity of T cells and mononuclears toward a chemokine [83]. Depletion of the microbiota in HF was associated with liver fibrosis due to LPS-stimulation of stellate cells and, however, promoting local iron sequestration through ferroportin-expressing phagocytes and hepatocyte-derived hepcidin acting as activator of conventional dendritic cells [83]. To note, about 30% of HF patients had no changes in the microbiota, while bacterial translocation from the gut microbiota and persistence of bacterial antigens were assumed to be responsible for systemic inflammation and HF decompensation. These facts indicate that the gut microbiota may influence liver architectonic and perfusion through other mechanisms, which need to be discovered [71]. For instance, there is evidence of the fact that the modifications to the microbiota by bile acid may provide signals through the intestine and bacterial products, as well as incretins and adipocytokines produced in the bowel, which affect lipid metabolism of hepatocytes [84,85]. Accumulation of triglycerides along with specific lipids including lysophosphatidylcholine and ceramides derive the toxic effects on hepatocytes and leads to mitochondrial and endoplasmic reticulum dysfunction due to oxidative stress, activation of signaling cascades and death receptors, and apoptosis [86]. Overall, the gut microbiota acts as modulator of oxidative stress and inflammatory response in liver tissue.

3.3. Adipose Tissue Dysfunction

Adipose tissue is involved in various changes in HF patients (inflammation, browning) and it is a source of mesenchymal stem cells and adipokines, which essentially regulate the energy metabolism of distant tissues including the liver [87,88,89]. Adipogenic liver transformation propagates local redox imbalance and activates in lipid-dependent deterioration of hepatocytes. Alterations in hepatocyte histology is associated with elevated expression of PPARγ, adipocyte protein, interleukin-6 (IL-6), interleukin-18 (IL-18), CD36 and adiponectin [90]. It appears that PPARα and PPARδ dysfunction is a key regulator, through which adipokines can mediate repair processes in the liver [91]. Nevertheless, altered autophagy/mitophagy and mitochondrial dysfunction may be attenuated by adiponectin in both ACLI and CCH [92]. It is possible that adiponectin induces autophagosome formation through AMP-activated protein kinase (AMPK)-dependent activation of Unc-51-like kinase 1, which subsequently leads to the removal of damaged mitochondria from hepatocytes [92]. Indeed, suppression of autophagy in white adipose tissues attenuated the liver fibrosis through adipose-liver crosstalk [93]. However, adiponectin protects liver injury by inactivating the TGF-beta-1/SMAD2 pathway and exerts an anti-fibrotic effect via the AMPK/STAT3 pathway [94]. However, adipokines (adiponectin, leptin) are thought to contribute to the anti-inflammatory effects of various hepatokines, such as apelin, adropin and fetuin-A by decreasing the local production of IL-6 and fibroblast growth factor 21 (FGF21), which prevent hepatic steatosis and fibrosis [95,96,97,98,99]. At the same time, apelin mediats Fas-induced liver injury in part via activation of c-Jun N-terminal kinases [100]. In parallel, FOXO transcription factors, which are directly modulated by insulin signaling in the liver, can be downregulated by IL-6, TNF-alpha and follistatin and can be upregulated by FGF21 [101]. Thus, adipokines that modulate the synthesis of IL-6, TNF-alpha, FGF21/Klotho and nitric oxide production via extracellular regulated kinase1/2 (p-ERK1/2) may improve liver metabolism by indirectly regulating glucose homeostasis and preventing mitochondrial dysfunction [102,103,104]. Meanwhile, FGF21 acts on adipocytes and renal cells to induce synthesis of angiotensin-converting enzyme 2 that inhibits hypertension and reverses vascular damage and microvascular inflammation [99]. Overall, the functional pleiotropism of adipose tissue affects its ability to synthesize and secretes numerous adipokines, which regulate liver metabolism, thermogenesis, microvascular inflammation, liver and remote tissue reparations, angiogenesis, insulin resistance, endothelial integrity, and causes not only multiple serious conditions, including adverse cardiac remodeling, adipose tissue dysfunction, liver fibrosis, but also mediates adaptive local changes in target organs.

3.4. Impaired Skeletal Muscles Metabolism

Skeletal muscle myopathy is a common condition of HF, especially in patients with HFrEF and HFmrEF, which is strongly associated with a decrease in effective perfusion [105]. However, skeletal muscle cells have endocrine capabilities and secrete a broad spectrum of regulatory proteins called myokines (myonectine, irisin, myoststin, FGF21, FGF15), which are involved in autocrine/paracrine regulation of distant organs and tissues, including the liver [106]. They are able to activate AMP-activated protein kinase and modulate its cooperation with the transcription factor nuclear respiratory factor 1, sirtuin-1 and the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α, and induce the expression of mitochondrial transcription factor-A genes that support mitochondrial protection [107,108,109]. Loss of a pool of these secreting proteins such as irisin, myonectin, FGF21 and growth differential factor-11 (GDF11) reduces the tissue-protective effect of myokines [110,111,112]. However, a precise understanding of the beneficial effects of myokines on cardiac hepatopathy appears to require further investigation.

3.5. Epigenetic Impact of Metabolic Comorbidities on Liver Tissue Modification

Epigenetic changes in DNA through DNA methylation, histone modifications and microRNA sequences are thought to be critical for specific changes in genes that coordinate several underlying molecular mechanisms in the pathogenesis of cardiac hepatopathy [113]. In addition, various metabolic comorbidities such as diabetes mellitus, insulin resistance and nonalcoholic fatty liver disease are thought to influence the reparative capacity of the liver through epigenetic changes in genes encoding adipokines, transport proteins (microsomal triglyceride transfer protein, patatin-like phospholipase domain-containing protein 3), PPAR-γ receptors and also genes involved in adipogenic/lipogenic regulation (homeostasis-associated gene, retinoid X receptor alpha gene, and liver X receptor alpha gene) [114,115,116,117]. However, epigenetic regulation of liver tissue susceptibility to acute and chronic damage in HF is the subject of further investigation.
Thus, the occurrence of cardiac hepatopathy is the result of several overlapping mechanisms, which include ischemia/reperfusion injury of liver tissue, passive fluid congestion, reduced hepatic blood with intrahepatic thrombosis, total body hypoxemia, and inability to utilize oxygen and metabolic components. These mechanisms are under close regulation of auto-paracrine and epigenetic influences. Increasing evidence suggests that interplay between hepatokines, adipokines and cardiokines mainly natriuretic peptides are crucial for the metabolic crosstalk between systemic and local myocardial/microvascular inflammation in HF and peripheral tissue damage in liver and some remote organs and tissues including kidney, spleen, skeletal muscle and adipose, tissue), but the direct underlying mechanisms linking advanced cardiac dysfunction and liver fibrosis remain not fully elucidated.

4. Plausible Role of Hepatokines in Cardiac Hepatopathy

4.1. Adropin

Adropin is a low molecular weight, multifunctional, membrane-bound peptide synthesized predominantly in the liver and brain [118]. The expression of adropin is regulated by dietary behavior and nutrients, as well as by various inflammatory cytokines and adipokines, including leptin [119,120]. There is interesting evidence of a link between the Energy Homeostasis Associated gene, which encodes adropin, energy homeostasis and lipid metabolism [119]. However, adropin mediates the expression of PPAR-γ receptor and hepatic lipogenic genes [120]. Adropin is expressed in numerous tissues, including liver, heart, brain, pancreatic tissue, kidney, small intestine, endothelial cells, colostrum and vessels [121].
Physiologically, adropin acts by binding to the orphan G protein-coupled receptor and the liver X receptor to suppress water deprivation and enhance glucose and lipid oxidation, respectively [122,123]. However, it remains unclear how adropin enhances intrahepatic metabolism and supports integrative intracellular signaling activities in the liver. One of the explanations concerns the ability of adropin to attenuate insulin-mediated regulation of glucose homeostasis and insulin resistance. Another assumption is based on the positive effect of adropin on the integrity of the endoplasmic reticulum through suppression of cAMP-activated protein kinase A and c-Jun N-terminal kinase activity in hepatocytes, resulting in decreased phosphorylation of the inositol triphosphate receptor and decreased secretion of NLRP3 inflammasome [121,122]. It is possible that all these factors reduce the efficacy of genes related to inflammation. There are numerous data on tissue-protective effects of adropin resulting from activation of the GPCR-MAPK-PDK4 pathway (protecting the heart and hepatocytes from metabolic dysfunction), VEGF receptor-2 (supporting vascular integrity, endothelial function, capillary density, and angiogenesis), PI3K-Akt and Erk1/2 pathways (promotion of nitric oxide production) and the MAPK and FOXO1 pathways (suppression of inflammation and attenuation of oxidative stress) [123,124,125,126,127,128,129].
In clinical practice, low adropin levels were detected in patients with abdominal obesity, diabetes mellitus, arterial hypertension, multifocal atherosclerosis, chronic kidney disease and chronic HF, whereas increased adropin levels have been found in acute HF and acute coronary syndrome [128,129,130,131,132]. Furthermore, circulating adropin levels were negatively correlated with cardiovascular disease risk in the general population [132,133,134,135,136]. There is a limited amount of strong evidence for a positive role of adropin in liver injury. Chen et al. (2019) [137] reported that adropin protects against acute liver injury through binding to Nrf2, mediating antioxidant capacity and attenuating hepatocyte necrosis via upregulating liver expression of Gclc, Gclm and Gpx1. Therefore, adropin has demonstrated its ability to reduce the local production of IL-6 and TNF-alpha, thereby suppressing the intensity of inflammatory response, along with attenuating mitochondrial dysfunction in hepatocytes and propagating fibrosis [125,138,139]. An experimental study by Skrzypski et al. (2022) [140] showed that exogenous adropin improved glucose control and restored the levels of elevated transaminases in peripheral blood without modulating insulin sensitivity in animals with type 2 diabetes mellitus and concomitant liver injury. However, supporting adropin synthesis in the liver is thought to be effective in liver protection. Indeed, there is evidence that activation of opioid μ-receptors and glucagon-like peptide 1 receptors in the liver can increase the circulating adropin pool, opening new perspectives for liver-protective therapy [141,142].

4.2. Fetuin-A

Fetuin-A (also known as alpha2-Heremans-Schmid glycoprotein) is a low molecular weight multifunctional protein synthesized predominantly by the liver [143]. Approximately 5% of the fetuin-A produced is extrahepatic localized. After extensive post-translational modifications of its single-chain precursor, Fetuin-A is recognized as a biologically stable form in the bloodstream and unfolds its biological potency [144]. Clearance of fetuin-A is provided by a widely distributed cysteine peptidase. The most important biological role of Fetuin-A is its participation in various metabolites (minerals, lipids) and binding of lectins [145]. Fetuin-A is involved in a number of pathophysiological regulations, such as insulin receptor signaling, adipocyte dysfunction and inflammation, liver fibrosis, lipid toxicity, triacylglycerol production, macrophage phenotype modification, promotion of angiogenesis, β-cell damage/apoptosis and TLR4 activation, which are critical for liver integrity and function [146,147,148]. Therefore, fetuin-A is responsible for downregulation of insulin receptor expression and TGF-beta signaling [149,150].
In the clinical setting, higher fetuin-A levels were strongly associated with insulin resistance, abdominal obesity, T2DM, extravascular calcification, asymptomatic atherosclerosis, cardiovascular disease, chronic kidney disease, nonalcoholic fatty liver disease and cognitive dysfunction [150,151,152,153,154,155]. It has been postulated that elevated fetuin-A levels may be an adaptive response to counteract the production of inflammatory cytokines [156]. In addition, there are conflicting data on an association between variability in circulating fetuin-A associated with single nucleotide polymorphisms in the fetuin-A-encoding AHSG gene and T2DM risk in the general population [157,158,159]. Whether the SNP can be associated with liver complications in HF remains uncertain. Meanwhile, circulating fetuin-A levels were sufficiently reduced (by 64%) in patients with acute liver failure compared with those who did not have liver failure [160]. Nevertheless, fetuin-A predicts progression of liver and vascular fibrosis in hemodynamically stable patients with cardiovascular disease and nonalcoholic fatty liver disease [161]. In contrast, there was no clear evidence that circulating fetuin-A levels have significant predictive value for liver fibrosis in patients without T2DM and cardiovascular disease [162]. Fetuin-A is thought to modulate an impact of dietary inflammatory potential on liver parenchymal integrity and fibrosis risk [163]. Possibly, in this way, this hapotokine attenuates a negative influence of circulating LPS/DNA from the gut microbiota on inflammatory changes in the liver by acting as a regulator of HMGB1 release from innate immune cells [164]. However, Tomita et al. (2022) [165] reported that low fetuin-A concentrations were found in the circulation of patients with HF compared with healthy subjects. Moreover, decreased fetuin-A concentrations were associated with hepatic hypoperfusion, but not with liver stiffness [165]. Finally, the authors found that HF patients with low fetuin-A concentrations and liver hypoperfusion had the lowest survival rate. Potentially, fetuin-A could be a new surrogate biomarker for cardiac hepatopathy with possible discriminatory value.

4.3. Alpha1-Microglobulin

Alpha1-microglobulin is a small, multifunctional circulating glycoprotein that belongs to the lipocalin family and is synthesized exclusively by the liver and abundantly released into the bloodstream [166,167]. Its major biological role involves endogenous protection against a broad spectrum of oxidants, including inhibition of proteinases, methemoglobin, cytochrome C, oxidized collagen I, oxidized low-density lipoprotein, free iron and mediation of tissue repair [168]. Alpha1-microglobulin acts as stimulator for APCs through activating Akt, NF-κB, and ERK signaling systems and, consequently, it enhances inflammation, migration and polarization of macrophages [23]. On the contrary, alpha1-microglobulin exerted its ability to suppress fibrogenesis-related mRNA expression in cultured macrophages and cardiac fibroblasts [23]. Intramyocardial AM administration in animals with acute myocardial infarction activated migration of macrophage, their infiltration of myocardial damage area, inflammatory response, and enhance matrix metalloproteinase-9 mRNA expression in the infarct area and peri-infarct zones, whereas disturbed fibrotic repair, then provoked acute cardiac rupture in acute myocardial infarction [23]. Alpha1-microglobulin is encoded by the alpha1-microglobulin bikunin precursor gene (AMBP), which also encodes bikunin, a structural protein of the extracellular matrix and a Kunitz-type plasma proteinase inhibitor [169]. Under physiological conditions, AMBP gene expression in the liver is regulated by hepatocyte nuclear factors and the Keap1/Nrf2 system. AMBP mRNA has also been detected in numerous tissues other than the liver, including the placenta, retina, cardiac muscle, skeletal muscle, kidney, lung and vasculature. Up-regulation of the AMBP gene has been found in numerous diseases characterized by increased ROS levels and circulating proteases [170,171,172]. AMBP functions as an intravascular and extravascular radical scavenger with high reduction activity and the ability to bind free heme groups, as well as chaperones [173,174]. In fact, AMBP downregulates the expression of apoptotic, inflammatory and stress-related genes, improves membrane permeability, prevents mitochondrial damage, and reduces renal and liver tissue damage from acute ischemia/hypoxia-induced injury [174,175,176]. Although AMBP is a liver-derived glycoprotein exclusively, its clinical significance has been better explored in acute kidney injury and acute nephrotoxicity than in ACLI [177,178]. However, the predictive value of AMBP in cardiac hepatopathy seems promising and requires further investigation.

4.4. Fibroblast Growth Factor-21

Fibroblast growth factor-21 (FGF21) is a stress-induced peptide produced mainly by the liver, but also by adipose tissue and skeletal muscle [179]. In the liver, it acts as a Klotho/β-Klotho cofactor and regulates mitochondrial oxidative activity and gluconeogenesis, increasing insulin sensitivity, decreasing plasma glucose levels, and modulating lipolytic activity [180]. In white adipose tissue (WAT), FGF21 regulates WAT browning along with brown adipocyte activation and lipolysis [180]. Moreover, FGF21 increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes, thus stimulating the expression of adiponectin in WAT [181]. Administration of FGF21 shows a wide range of beneficial responses in animals with obesity-related metabolic disorders, including reduction of fat mass, alleviation of postprandial hyperglycemia, attenuation of insulin resistance, improvement of dyslipidemia, hepatic autophagy and prevention of steatohepatitis via histone demethylase Jumonji-D3 (JMJD3/KDM6B) [182,183]. Moreover, FGF21 deficiency promotes the occurrence of steatosis, inflammation, oxidative stress, autophagy, hepatocyte damage and excessive fibrosis in the liver [184]. Although protective effects of FGF21 have been attributed to the support of endothelial integrity and function, attenuation of lipid accumulation and atherosclerotic plaque formation and the inhibition of cardiomyocyte apoptosis and regulation of the oxidative stress-inflammation cascade [185], the protective mechanisms for the liver have not been fully elucidated. Indeed, FGF21 has demonstrated its ability to remarkably decrease the levels of circulating transaminases, IL-6 and TNF-alpha [186]. Notably, there is evidence for the involvement of SIRT1 autophagy signaling in protective and antifibrotic effects of FGF21 in response to acute liver injury [187,188]. Besides, FGF21 seems to have the ability to suppress ferroptosis and consequently to induce significant protection of hepatocytes from iron overload-induced mitochondrial damage leading to necrosis and excessive fibrosis [189]. However, FGF21 can regulate PGC-1α expression in hepatocytes and attenuate apoptosis and fibrosis-related gene expression in the liver [190]. The role of FGF21 interactions with the central nervous system in the context of liver injury is currently under scientific debate [191]. It is possible that FGF21 could link altered eating behavior to cardiac hepatopathy in HF patients with cardiac cachexia, as beta-adrenergic stimulation of thermogenic gene expression requires FGF21 [192]. Last but not least, FGF21 mediated the activation of ERK1/ERK2 in WAT, liver and skeletal muscle, mediating the systemic protective effects on energy metabolism by improving insulin sensitivity [193]. The clinical significance of these findings needs to be investigated in detail in the future.

4.5. Selenoprotein P

Selenoprotein P is a liver-derived secretory redox protein with an intrinsic thioredoxin domain whose major biological function is the transfer of selenium to intracellular glutathione peroxidases [194]. Selenoprotein P is considered as a hepatokine with antioxidant capabilities that prevents mitochondrial dysfunction and oxidative stress in numerous tissues and organs including the liver [195,196]. Therefore, in the physiological state, selenoprotein P regulates systemic energy metabolism and pancreatic β-cell function, and prevents its apoptosis by suppressing caspase-3 activity [197]. In the pathological state, low levels of selenoprotein P were associated with impaired insulin sensitivity, altered angiogenesis and cell proliferation through inhibition of vascular endothelial growth factor [198,199]. The systemic tissue-protective effects of selenoprotein P are promoted by phosphoinositide 3-kinase/Akt and Erk 1/2 signaling pathways [200].
In ACLI, selenoprotein P is involved in pre- and post-treatment [201]. Circulating levels of selenoprotein P show a tendency to decrease in patients with acute and chronic liver disease, including acute liver injury, simple steatosis and nonalcoholic liver disease [190]. However, selenoprotein P levels were significantly increased in patients with HF with liver hypoperfusion compared with patients without this disease [202]. Interestingly, there were no significant differences between selenoprotein P levels in HF patients with and without liver congestion [203]. Selenoprotein P supplementation in patients with HF and ACLI is being actively studied. The majority of patients involved in the studies had acute alcoholic access [204,205]. Of note, no significant differences in liver structure measured by magnetic resonance imaging were found in patients with different metabolic diseases depending on their selenoprotein P status [206]. Finally, the clinical outlook for selenoprotein P seems promising, whereas there are limited data for its role in cardiac hepatopathy.
Thus, hepatokines exert local hepatic effects and promote effects on remote tissues including myocardium, vessels, skeletal muscles, and pancreas (Table 1). Although hepatokines play a crucial role as metabolic regulator of liver function and other organs in HF, their diagnostic and predictive abilities for HF require deep investigation with subsequent validation and comparison with conventional circulating biomarkers of liver injury and cardiac remodeling. Therefore, there is no sufficient data of plausible difference of sensitivity and specificity of these biomarkers in different phenotypes of cardiac hepatopathy.
More investigations in the future are needed to clearly elucidate whether hepatokines are promising molecules with predictive potency for patients with HF and cardiac hepatopathy.

4.6. Hepatokines and Liver Drug Metabolism

Cardio-hepatic interactions in HF implicated in liver drug metabolism and mediated toxicity impact of the agents on several tissues and organs [207]. Abnormalities in drug metabolism may affect intrinsic activity of metabolic enzymes including methylation, oxidation, hydroxylation, conjugation, reductions in the synthesis of transporters, bioavailability of active metabolites of some drugs in intestine and their hepatic clearance, and binding with plasma proteins [208]. Although there is clear the Food and Drug Administration and the European Medicines Evaluation Agency guidelines for the administration of several pharmacotherapies in renal dysfunction, specific recommendations regarding personally adjusted medication dose in patients with cardiac hepatopathy are not updated regularly [209]. To note, many potential drug interactions and co-administered agents may suppress hepatic metabolism and maintain liver injury in either hemodynamically stable or are unstable patients with acute/chronic HF [30]. In this context, the utilization of hepatokines reflecting of hepatocyte metabolism appears to be promising. For instance, animal study has shown that fetuin-A predicted laboratory signs of hepatotoxicity and the liver tissue infiltration of monocytes in acetaminophen-induced liver injury [209]. Less known about an influence of HF guideline-recommended treatment on hepatokines. SGLT2 inhibitors along with antagonists of renin-angiotensin-aldosterone antagonists and beta-blockers demonstrated their ability to increase in adropin levels [210]. In fact, the levels of hepatokines may be modulated by conventional HF therapy, but there is not fully understood, whether it would be powerful tool for ongoing HF drug toxicity monitoring and surrogate indicator of early response on the treatment with further changes in drug administration regime to prevent drug toxicity.

5. Conclusions

Hepatokines may play a crucial pathogenetic role in onset and progression of cardiac hepatopathy. They are considered novel diagnostic and predictive markers for both phenotypes of cardiac hepatopathy. The most clinically relevant hepatokines linking clinical outcomes of HF and liver structure abnormalities are adropin in ACLI and fetuin-A and FGF21 in CCH. On the contrary, FGF21 and selenoprotein P appear to be the most promising therapeutic targets among the other hepatokines in patients with any forms of cardiac hepatopathy.

Author Contributions

Conceptualization, A.E.B. and M.L.; methodology, T.A.B.; software, A.A.B. and Z.O.; validation, A.E.B. and M.L.; formal analysis, T.A.B.; investigation, A.A.B., Z.O., T.A.B., M.L. and A.E.B.; resources, T.A.B.; data curation, A.A.B.; writing—original draft preparation, A.A.B., Z.O., T.A.B., M.L. and A.E.B.; writing—review and editing, A.A.B., Z.O., T.A.B., E.B., M.L. and A.E.B.; supervision, A.E.B.; project administration, A.A.B. and E.B. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Emmons-Bell, S.; Johnson, C.; Roth, G. Prevalence, incidence and survival of heart failure: A systematic review. Heart 2022, 108, 1351–1360. [Google Scholar] [CrossRef] [PubMed]
  2. Van Riet, E.E.; Hoes, A.W.; Wagenaar, K.P.; Limburg, A.; Landman, M.A.; Rutten, F.H. Epidemiology of heart failure: The prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur. J. Heart Fail. 2016, 18, 242–252. [Google Scholar] [CrossRef] [PubMed]
  3. Cvijic, M.; Rib, Y.; Danojevic, S.; Radulescu, C.I.; Nazghaidze, N.; Vardas, P. Heart failure with mildly reduced ejection fraction: From diagnosis to treatment. Gaps and dilemmas in current clinical practice. Heart Fail. Rev. 2022. [Google Scholar] [CrossRef] [PubMed]
  4. Echouffo-Tcheugui, J.B.; Erqou, S.; Butler, J.; Yancy, C.W.; Fonarow, G.C. Assessing the Risk of Progression from Asymptomatic Left Ventricular Dysfunction to Overt Heart Failure: A Systematic Overview and Meta-Analysis. JACC Heart Fail. 2016, 4, 237–248. [Google Scholar] [CrossRef] [PubMed]
  5. Gori, M.; Redfield, M.M.; Calabrese, A.; Canova, P.; Cioffi, G.; De Maria, R.; Grosu, A.; Fontana, A.; Iacovoni, A.; Ferrari, P.; et al. Is mild asymptomatic left ventricular systolic dysfunction always predictive of adverse events in high-risk populations? Insights from the DAVID-Berg study. Eur. J. Heart Fail. 2018, 20, 1540–1548. [Google Scholar] [CrossRef][Green Version]
  6. Pandhi, J.; Gottdiener, J.S.; Bartz, T.M.; Kop, W.J.; Mehra, M.R. Comparison of characteristics and outcomes of asymptomatic versus symptomatic left ventricular dysfunction in subjects 65 years old or older (from the Cardiovascular Health Study). Am. J. Cardiol. 2011, 107, 1667–1674. [Google Scholar] [CrossRef][Green Version]
  7. Vyskocilova, K.; Spinarova, L.; Spinar, J.; Mikusova, T.; Vitovec, J.; Malek, J.; Malek, F.; Linhart, A.; Fedorco, M.; Widimsky, P.; et al. Prevalence and clinical significance of liver function abnormalities in patients with acute heart failure. Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc. Czech Repub. 2015, 159, 429–436. [Google Scholar] [CrossRef][Green Version]
  8. Biegus, J.; Hillege, H.L.; Postmus, D.; Valente, M.A.; Bloomfield, D.M.; Cleland, J.G.; Cotter, G.; Davison, B.A.; Dittrich, H.C.; Fiuzat, M.; et al. Abnormal liver function tests in acute heart failure: Relationship with clinical characteristics and outcome in the PROTECT study. Eur. J. Heart Fail. 2016, 18, 830–839. [Google Scholar] [CrossRef][Green Version]
  9. Samsky, M.D.; Dunning, A.; DeVore, A.D.; Schulte, P.J.; Starling, R.C.; Tang, W.H.; Armstrong, P.W.; Ezekowitz, J.A.; Butler, J.; McMurray, J.J.; et al. Liver function tests in patients with acute heart failure and associated outcomes: Insights from ASCEND-HF. Eur. J. Heart Fail. 2016, 18, 424–432. [Google Scholar] [CrossRef]
  10. Ambrosy, A.P.; Vaduganathan, M.; Huffman, M.D.; Khan, S.; Kwasny, M.J.; Fought, A.J.; Maggioni, A.P.; Swedberg, K.; Konstam, M.A.; Zannad, F.; et al. Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: An analysis of the EVEREST trial. Eur. J. Heart Fail. 2012, 14, 302–311. [Google Scholar] [CrossRef]
  11. Wang, H.Y.; Huang, Y.; Chen, X.Z.; Zhang, Z.L.; Gui, C. Prognostic potential of liver injury in patients with dilated cardiomyopathy: A retrospective study. Eur. J. Med. Res. 2022, 27, 237. [Google Scholar] [CrossRef]
  12. Ambrosy, A.P.; Vaduganathan, M.; Mentz, R.J.; Greene, S.J.; Subačius, H.; Konstam, M.A.; Maggioni, A.P.; Swedberg, K.; Gheorghiade, M. Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: Insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial. Am. Heart J. 2013, 165, 216–225. [Google Scholar] [CrossRef]
  13. Meng, W.; Wang, L.; Fan, H.; Mao, S.; Song, X.; Zhang, Z. Total Bilirubin Level is Associated with the Risk of Left Atrial Appendage Thrombosis in Patients with Non-Valvular Atrial Fibrillation. Glob. Heart 2022, 17, 90. [Google Scholar] [CrossRef]
  14. Xanthopoulos, A.; Starling, R.C.; Kitai, T.; Triposkiadis, F. Heart Failure and Liver Disease: Cardiohepatic Interactions. JACC Heart Fail. 2019, 7, 87–97. [Google Scholar] [CrossRef]
  15. Laribi, S.; Mebazaa, A. Cardiohepatic syndrome: Liver injury in decompensated heart failure. Curr. Heart Fail. Rep. 2014, 11, 236–240. [Google Scholar] [CrossRef]
  16. Branchereau, M.; Burcelin, R.; Heymes, C. The gut microbiome and heart failure: A better gut for a better heart. Rev. Endocr. Metab. Disord. 2019, 20, 407–414. [Google Scholar] [CrossRef]
  17. El Hadi, H.; Di Vincenzo, A.; Vettor, R.; Rossato, M. Relationship between Heart Disease and Liver Disease: A Two-Way Street. Cells 2020, 9, 567. [Google Scholar] [CrossRef][Green Version]
  18. Gheorghiade, M.; Follath, F.; Ponikowski, P.; Barsuk, J.H.; Blair, J.E.; Cleland, J.G.; Dickstein, K.; Drazner, M.H.; Fonarow, G.C.; Jaarsma, T.; et al. Assessing and grading congestion in acute heart failure: A scientific statement from the acute heart failure committee of the heart failure association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine. Eur. J. Heart Fail. 2010, 12, 423–433. [Google Scholar] [CrossRef]
  19. Çağlı, K.; Başar, F.N.; Tok, D.; Turak, O.; Başar, Ö. How to interpret liver function tests in heart failure patients? Turk. J. Gastroenterol. 2015, 26, 197–203. [Google Scholar] [CrossRef][Green Version]
  20. Fortea, J.I.; Puente, Á.; Cuadrado, A.; Huelin, P.; Pellón, R.; González Sánchez, F.J.; Mayorga, M.; Cagigal, M.L.; García Carrera, I.; Cobreros, M.; et al. Congestive Hepatopathy. Int. J. Mol. Sci. 2020, 21, 49420. [Google Scholar] [CrossRef]
  21. De Gonzalez, A.K.K.; Lefkowitch, J.H. Heart Disease and the Liver: Pathologic Evaluation. Gastroenterol. Clin. North Am. 2017, 46, 421–435. [Google Scholar] [CrossRef] [PubMed]
  22. Fouad, Y.M.; Yehia, R. Hepato-cardiac disorders. World J. Hepatol. 2014, 6, 41–54. [Google Scholar] [CrossRef] [PubMed]
  23. Hakuno, D.; Kimura, M.; Ito, S.; Satoh, J.; Nakashima, Y.; Horie, T.; Kuwabara, Y.; Nishiga, M.; Ide, Y.; Baba, O.; et al. Hepatokine α1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial Infarction. Sci. Rep. 2018, 8, 16749. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Kavoliuniene, A.; Vaitiekiene, A.; Cesnaite, G. Congestive hepatopathy and hypoxic hepatitis in heart failure: A cardiologist’s point of view. Int. J. Cardiol. 2013, 166, 554–558. [Google Scholar] [CrossRef]
  25. Birrer, R.; Takuda, Y.; Takara, T. Hypoxic hepatopathy: Pathophysiology and prognosis. Intern. Med. 2007, 46, 1063–1070. [Google Scholar] [CrossRef][Green Version]
  26. Mauriello, J.N.; Straughan, M.M. Right-Sided Heart Failure and the Liver. Crit. Care Nurs. Clin. North Am. 2022, 34, 341–350. [Google Scholar] [CrossRef]
  27. Correale, M.; Tarantino, N.; Petrucci, R.; Tricarico, L.; Laonigro, I.; Di Biase, M.; Brunetti, N.D. Liver disease and heart failure: Back and forth. Eur. J. Intern. Med. 2018, 48, 25–34. [Google Scholar] [CrossRef]
  28. Megalla, S.; Holtzman, D.; Aronow, W.S.; Nazari, R.; Korenfeld, S.; Schwarcz, A.; Goldberg, Y.; Spevack, D.M. Predictors of cardiac hepatopathy in patients with right heart failure. Med. Sci. Monit. 2011, 17, CR537–CR541. [Google Scholar] [CrossRef][Green Version]
  29. Allen, L.A.; Felker, G.M.; Pocock, S.; McMurray, J.J.; Pfeffer, M.A.; Swedberg, K.; CHARM Investigators. Liver function abnormalities and outcome in patients with chronic heart failure: Data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Eur. J. Heart Fail. 2009, 11, 170–177. [Google Scholar] [CrossRef][Green Version]
  30. Benincasa, G.; Cuomo, O.; Vasco, M.; Vennarecci, G.; Canonico, R.; Della Mura, N.; Alfano, R.; Napoli, C. Epigenetic-sensitive challenges of cardiohepatic interactions: Clinical and therapeutic implications in heart failure patients. Eur. J. Gastroenterol. Hepatol. 2021, 33, 1247–1253. [Google Scholar] [CrossRef]
  31. Seeto, R.K.; Fenn, B.; Rockey, D.C. Ischemic hepatitis: Clinical presentation and pathogenesis. Am. J. Med. 2000, 109, 109–113. [Google Scholar] [CrossRef]
  32. Lightsey, J.M.; Rockey, D.C. Current concepts in ischemic hepatitis. Curr. Opin. Gastroenterol. 2017, 33, 158–163. [Google Scholar] [CrossRef]
  33. Wisse, E.; Jacobs, F.; Topal, B.; Frederik, P.; De Geest, B. The size of endothelial fenestrae in human liver sinusoids: Implications for hepatocyte-directed gene transfer. Gene. Ther. 2008, 15, 1193–1199. [Google Scholar] [CrossRef][Green Version]
  34. Sundaram, V.; Fang, J.C. Gastrointestinal and Liver Issues in Heart Failure. Circulation 2016, 133, 1696–1703. [Google Scholar] [CrossRef]
  35. Goncalvesova, E.; Kovacova, M. Heart failure affects liver morphology and function. What are the clinical implications? Bratisl. Lek. Listy. 2018, 119, 98–102. [Google Scholar] [CrossRef][Green Version]
  36. Moreira-Silva, S.; Urbano, J.; Moura, M.C.; Ferreira-Coimbra, J.; Bettencourt, P.; Pimenta, J. Liver cytolysis in acute heart failure: What does it mean? Clinical profile and outcomes of a prospective hospital cohort. Int. J. Cardiol. 2016, 221, 422–427. [Google Scholar] [CrossRef]
  37. Møller, S.; Dümcke, C.W.; Krag, A. The heart and the liver. Expert. Rev. Gastroenterol. Hepatol. 2009, 3, 51–64. [Google Scholar] [CrossRef]
  38. Samsky, M.D.; Patel, C.B.; DeWald, T.A.; Smith, A.D.; Felker, G.M.; Rogers, J.G.; Hernandez, A.F. Cardiohepatic interactions in heart failure: An overview and clinical implications. J. Am. Coll. Cardiol. 2013, 61, 2397–2405. [Google Scholar] [CrossRef][Green Version]
  39. Scalzo, N.; Canastar, M.; Lebovics, E. Part 2: Disease of the Heart and Liver: A Relationship That Cuts Both Ways. Cardiol. Rev. 2022, 30, 161–166. [Google Scholar] [CrossRef]
  40. Jaeschke, H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 284, G15–G26. [Google Scholar] [CrossRef]
  41. Lee, W.Y.; Lee, J.S.; Lee, S.M. Protective effects of combined ischemic preconditioning and ascorbic acid on mitochondrial injury in hepatic ischemia/reperfusion. J. Surg. Res. 2007, 142, 45–52. [Google Scholar] [CrossRef] [PubMed]
  42. Hasegawa, T.; Malle, E.; Farhood, A.; Jaeschke, H. Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: Attenuation by ischemic preconditioning. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G760–G767. [Google Scholar] [CrossRef] [PubMed][Green Version]
  43. Jin, L.M.; Liu, Y.X.; Zhou, L.; Xie, H.Y.; Feng, X.W.; Li, H.; Zheng, S.S. Ischemic preconditioning attenuates morphological and biochemical changes in hepatic ischemia/reperfusion in rats. Pathobiology 2010, 77, 136–146. [Google Scholar] [CrossRef] [PubMed]
  44. Mendes-Braz, M.; Elias-Miró, M.; Jiménez-Castro, M.B.; Casillas-Ramírez, A.; Ramalho, F.S.; Peralta, C. The current state of knowledge of hepatic ischemia-reperfusion injury based on its study in experimental models. J. Biomed. Biotechnol. 2012, 2012, 298657. [Google Scholar] [CrossRef][Green Version]
  45. Sun, C.K.; Zhang, X.Y.; Zimmermann, A.; Davis, G.; Wheatley, A.M. Effect of ischemia-reperfusion injury on the microcirculation of the steatotic liver of the Zucker rat. Transplantation 2001, 72, 1625–1631. [Google Scholar] [CrossRef]
  46. Nastos, C.; Kalimeris, K.; Papoutsidakis, N.; Tasoulis, M.K.; Lykoudis, P.M.; Theodoraki, K.; Nastou, D.; Smyrniotis, V.; Arkadopoulos, N. Global consequences of liver ischemia/reperfusion injury. Oxid. Med. Cell. Longev. 2014, 2014, 906965. [Google Scholar] [CrossRef][Green Version]
  47. Uhlmann, D.; Glasser, S.; Gaebel, G.; Armann, B.; Ludwig, S.; Tannapfel, A.; Hauss, J.; Witzigmann, H. Improvement of postischemic hepatic microcirculation after endothelin A receptor blockade—Endothelin antagonism influences platelet-endothelium interactions. J. Gastrointest. Surg. 2005, 9, 187–197. [Google Scholar] [CrossRef]
  48. Kuwano, A.; Kurokawa, M.; Kohjima, M.; Imoto, K.; Tashiro, S.; Suzuki, H.; Tanaka, M.; Okada, S.; Kato, M.; Ogawa, Y.; et al. Microcirculatory disturbance in acute liver injury. Exp. Ther. Med. 2021, 21, 596. [Google Scholar] [CrossRef]
  49. Tanaka, M.; Tanaka, K.; Masaki, Y.; Miyazaki, M.; Kato, M.; Kotoh, K.; Enjoji, M.; Nakamuta, M.; Takayanagi, R. Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats. Int. J. Mol. Med. 2014, 33, 254–262. [Google Scholar] [CrossRef][Green Version]
  50. Zhang, X.; Jiang, W.; Zhou, A.L.; Zhao, M.; Jiang, D.R. Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3β signaling pathway. World J. Gastroenterol. 2017, 23, 3839–3849. [Google Scholar] [CrossRef]
  51. Quesnelle, K.M.; Bystrom, P.V.; Toledo-Pereyra, L.H. Molecular responses to ischemia and reperfusion in the liver. Arch. Toxicol. 2015, 89, 651–657. [Google Scholar] [CrossRef]
  52. Wang, X.T.; Tang, Y.B.; Lin, Q.Q.; Wang, X.Y.; Song, Z.Y.; Hao, M.L.; Qian, W.; Wang, W.T. Role of autophagy in liver injury induced by lung ischemia/reperfusion in rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2022, 38, 102–107. (In Chinese) [Google Scholar] [CrossRef]
  53. Zhao, J.; Chen, X.D.; Yan, Z.Z.; Huang, W.F.; Liu, K.X.; Li, C. Gut-Derived Exosomes Induce Liver Injury After Intestinal Ischemia/Reperfusion by Promoting Hepatic Macrophage Polarization. Inflammation 2022, 45, 2325–2338. [Google Scholar] [CrossRef]
  54. Ding, W.; Duan, Y.; Qu, Z.; Feng, J.; Zhang, R.; Li, X.; Sun, D.; Zhang, X.; Lu, Y. Acidic Microenvironment Aggravates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating M1-Polarization Through Regulating PPAR-γ Signal. Front. Immunol. 2021, 12, 697362. [Google Scholar] [CrossRef]
  55. Chen, L.Y.; Yang, B.; Zhou, L.; Ren, F.; Duan, Z.P.; Ma, Y.J. Promotion of mitochondrial energy metabolism during hepatocyte apoptosis in a rat model of acute liver failure. Mol. Med. Rep. 2015, 12, 5035–5041. [Google Scholar] [CrossRef][Green Version]
  56. Teodoro, J.S.; Da Silva, R.T.; Machado, I.F.; Panisello-Roselló, A.; Roselló-Catafau, J.; Rolo, A.P.; Palmeira, C.M. Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria. Cells 2022, 11, 688. [Google Scholar] [CrossRef]
  57. Tacke, F.; Zimmermann, H.W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 2014, 60, 1090–1096. [Google Scholar] [CrossRef][Green Version]
  58. Baeck, C.; Wei, X.; Bartneck, M.; Fech, V.; Heymann, F.; Gassler, N.; Hittatiya, K.; Eulberg, D.; Luedde, T.; Trautwein, C.; et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology 2014, 59, 1060–1072. [Google Scholar] [CrossRef]
  59. Sun, Y.Y.; Li, X.F.; Meng, X.M.; Huang, C.; Zhang, L.; Li, J. Macrophage Phenotype in Liver Injury and Repair. Scand. J. Immunol. 2017, 85, 166–174. [Google Scholar] [CrossRef][Green Version]
  60. Ehling, J.; Bartneck, M.; Wei, X.; Gremse, F.; Fech, V.; Möckel, D.; Baeck, C.; Baeck, C.; Hittatiya, K.; Eulberg, D.; et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014, 63, 1960–1971. [Google Scholar] [CrossRef][Green Version]
  61. Bartneck, M.; Schrammen, P.L.; Möckel, D.; Govaere, O.; Liepelt, A.; Krenkel, O.; Ergen, C.; McCain, M.V.; Eulberg, D.; Luedde, T.; et al. The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers. Cell Mol. Gastroenterol. Hepatol. 2019, 7, 371–390. [Google Scholar] [CrossRef] [PubMed][Green Version]
  62. Ko, S.; Russell, J.O.; Molina, L.M.; Monga, S.P. Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns. Annu. Rev. Pathol. 2020, 15, 23–50. [Google Scholar] [CrossRef] [PubMed][Green Version]
  63. Ma, X.; McKeen, T.; Zhang, J.; Ding, W.X. Role and Mechanisms of Mitophagy in Liver Diseases. Cells 2020, 9, 837. [Google Scholar] [CrossRef] [PubMed][Green Version]
  64. Jing, Z.T.; Liu, W.; Xue, C.R.; Wu, S.X.; Chen, W.N.; Lin, X.J.; Lin, X. AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury. Am. J. Physiol. Gastrointest. Liver. Physiol. 2019, 316, G387–G396. [Google Scholar] [CrossRef] [PubMed]
  65. Liu, W.; Jing, Z.T.; Xue, C.R.; Wu, S.X.; Chen, W.N.; Lin, X.J.; Lin, X. PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. Toxicol. Appl. Pharmacol. 2019, 381, 114729. [Google Scholar] [CrossRef]
  66. Matsuzaki, K. Smad phosphoisoform signals in acute and chronic liver injury: Similarities and differences between epithelial and mesenchymal cells. Cell Tissue Res. 2012, 347, 225–243. [Google Scholar] [CrossRef][Green Version]
  67. Yoshida, K.; Matsuzaki, K. Differential Regulation of TGF-β/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries. Front. Physiol. 2012, 3, 53. [Google Scholar] [CrossRef][Green Version]
  68. Chen, L.D.; Wu, R.H.; Huang, Y.Z.; Chen, M.X.; Zeng, A.M.; Zhuo, G.F.; Xu, F.S.; Liao, R.; Lin, Q.C. The role of ferroptosis in chronic intermittent hypoxia-induced liver injury in rats. Sleep Breath. 2020, 24, 1767–1773. [Google Scholar] [CrossRef]
  69. Liu, Z.L.; Huang, Y.P.; Wang, X.; He, Y.X.; Li, J.; Li, B. The role of ferroptosis in chronic intermittent hypoxia-induced cognitive impairment. Sleep Breath. 2023. [Google Scholar] [CrossRef]
  70. Zheng, Z.; Wang, B. The Gut-Liver Axis in Health and Disease: The Role of Gut Microbiota-Derived Signals in Liver Injury and Regeneration. Front. Immunol. 2021, 12, 775526. [Google Scholar] [CrossRef]
  71. Trebicka, J.; Macnaughtan, J.; Schnabl, B.; Shawcross, D.L.; Bajaj, J.S. The microbiota in cirrhosis and its role in hepatic decompensation. J. Hepatol. 2021, 75 (Suppl. 1), S67–S81. [Google Scholar] [CrossRef]
  72. Liu, H.X.; Keane, R.; Sheng, L.; Wan, Y.J. Implications of microbiota and bile acid in liver injury and regeneration. J. Hepatol. 2015, 63, 1502–1510. [Google Scholar] [CrossRef][Green Version]
  73. Baker, S.S.; Baker, R.D. Gut Microbiota and Liver Injury (II): Chronic Liver Injury. Adv. Exp. Med. Biol. 2020, 1238, 39–54. [Google Scholar] [CrossRef]
  74. Giuffrè, M.; Campigotto, M.; Campisciano, G.; Comar, M.; Crocè, L.S. A story of liver and gut microbes: How does the intestinal flora affect liver disease? A review of the literature. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 318, G889–G906. [Google Scholar] [CrossRef]
  75. Behary, J.; Amorim, N.; Jiang, X.T.; Raposo, A.; Gong, L.; McGovern, E.; Ibrahim, R.; Chu, F.; Stephens, C.; Jebeili, H.; et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat. Commun. 2021, 12, 187. [Google Scholar] [CrossRef]
  76. Fukui, H.; Brauner, B.; Bode, J.C.; Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: Reevaluation with an improved chromogenic assay. J. Hepatol. 1991, 12, 162–169. [Google Scholar] [CrossRef]
  77. Bellot, P.; García-Pagán, J.C.; Francés, R.; Abraldes, J.G.; Navasa, M.; Pérez-Mateo, M.; Such, J.; Bosch, J. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010, 52, 2044–2052. [Google Scholar] [CrossRef]
  78. Spadoni, I.; Zagato, E.; Bertocchi, A.; Paolinelli, R.; Hot, E.; Di Sabatino, A.; Caprioli, F.; Bottiglieri, L.; Oldani, A.; Viale, G.; et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015, 350, 830–834. [Google Scholar] [CrossRef]
  79. La Villa, G.; Gentilini, P. Hemodynamic alterations in liver cirrhosis. Mol. Aspects Med. 2008, 29, 112–118. [Google Scholar] [CrossRef]
  80. Chu, C.J.; Lee, F.Y.; Wang, S.S.; Chang, F.Y.; Lin, H.C.; Lu, R.H.; Chan, C.C.; Lee, S.D. Splanchnic endotoxin levels in cirrhotic rats induced by carbon tetrachloride. Zhonghua Yi Xue Za Zhi 2000, 63, 196–204. [Google Scholar]
  81. Krishnan, S.; Ding, Y.; Saedi, N.; Choi, M.; Sridharan, G.V.; Sherr, D.H.; Yarmush, M.L.; Alaniz, R.C.; Jayaraman, A.; Lee, K. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Rep. 2018, 23, 1099–1111. [Google Scholar] [CrossRef] [PubMed]
  82. Chen, S.; Henderson, A.; Petriello, M.C.; Romano, K.A.; Gearing, M.; Miao, J.; Schell, M.; Sandoval-Espinola, W.J.; Tao, J.; Sha, B.; et al. Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metab. 2019, 30, 1141–1151.e5. [Google Scholar] [CrossRef] [PubMed]
  83. Bessman, N.J.; Mathieu, J.R.R.; Renassia, C.; Zhou, L.; Fung, T.C.; Fernandez, K.C.; Austin, C.; Moeller, J.B.; Zumerle, S.; Louis, S.; et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science 2020, 368, 186–189. [Google Scholar] [CrossRef] [PubMed]
  84. Marra, F.; Svegliati-Baroni, G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 2018, 68, 280–295. [Google Scholar] [CrossRef] [PubMed]
  85. Winston, J.A.; Theriot, C.M. Diversification of host bile acids by members of the gut microbiota. Gut. Microbes 2020, 11, 158–171. [Google Scholar] [CrossRef]
  86. Weiss, T.S.; Lupke, M.; Ibrahim, S.; Buechler, C.; Lorenz, J.; Ruemmele, P.; Hofmann, U.; Melter, M.; Dayoub, R. Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways. PLoS ONE 2017, 12, e0184282. [Google Scholar] [CrossRef][Green Version]
  87. Teshima, T.; Matsumoto, H.; Michishita, M.; Matsuoka, A.; Shiba, M.; Nagashima, T.; Koyama, H. Allogenic Adipose Tissue-Derived Mesenchymal Stem Cells Ameliorate Acute Hepatic Injury in Dogs. Stem Cells Int. 2017, 2017, 3892514. [Google Scholar] [CrossRef]
  88. Kim, M.D.; Kim, S.S.; Cha, H.Y.; Jang, S.H.; Chang, D.Y.; Kim, W.; Suh-Kim, H.; Lee, J.H. Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis. Exp. Mol. Med. 2014, 46, e110. [Google Scholar] [CrossRef][Green Version]
  89. Berezin, A.E.; Berezin, A.A. Impaired function of fibroblast growth factor 23/Klotho protein axis in prediabetes and diabetes mellitus: Promising predictor of cardiovascular risk. Diabetes Metab. Syndr. 2019, 13, 2549–2556. [Google Scholar] [CrossRef]
  90. Lakhani, H.V.; Sharma, D.; Dodrill, M.W.; Nawab, A.; Sharma, N.; Cottrill, C.L.; Shapiro, J.I.; Sodhi, K. Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease. Int. J. Med. Sci. 2018, 15, 1591–1599. [Google Scholar] [CrossRef][Green Version]
  91. Li, T.H.; Yang, Y.Y.; Huang, C.C.; Liu, C.W.; Tsai, H.C.; Lin, M.W.; Tsai, C.Y.; Huang, S.F.; Wang, Y.W.; Lee, T.Y.; et al. Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis. Clin. Sci. 2019, 133, 531–544. [Google Scholar] [CrossRef]
  92. Lin, Z.; Wu, F.; Lin, S.; Pan, X.; Jin, L.; Lu, T.; Shi, L.; Wang, Y.; Xu, A.; Li, X. Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice. J. Hepatol. 2014, 61, 825–831. [Google Scholar] [CrossRef]
  93. Sakane, S.; Hikita, H.; Shirai, K.; Myojin, Y.; Sasaki, Y.; Kudo, S.; Fukumoto, K.; Mizutani, N.; Tahata, Y.; Makino, Y.; et al. White Adipose Tissue Autophagy and Adipose-Liver Crosstalk Exacerbate Nonalcoholic Fatty Liver Disease in Mice. Cell. Mol. Gastroenterol. Hepatol. 2021, 12, 1683–1699. [Google Scholar] [CrossRef]
  94. Wang, H.; Zhang, H.; Zhang, Z.; Huang, B.; Cheng, X.; Wang, D.; la Gahu, Z.; Xue, Z.; Da, Y.; Li, D.; et al. Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury. Sci. Rep. 2016, 6, 19445. [Google Scholar] [CrossRef]
  95. Clemens, M.M.; Kennon-McGill, S.; Vazquez, J.H.; Stephens, O.W.; Peterson, E.A.; Johann, D.J.; Allard, F.D.; Yee, E.U.; McCullough, S.S.; James, L.P.; et al. Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk. Acta Pharm. Sin. B 2021, 11, 3836–3846. [Google Scholar] [CrossRef]
  96. Tilg, H.; Kaser, A.; Moschen, A.R. How to modulate inflammatory cytokines in liver diseases. Liver Int. 2006, 26, 1029–1039. [Google Scholar] [CrossRef]
  97. Wolf, A.M.; Wolf, D.; Avila, M.A.; Moschen, A.R.; Berasain, C.; Enrich, B.; Rumpold, H.; Tilg, H. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J. Hepatol. 2006, 44, 537–543. [Google Scholar] [CrossRef][Green Version]
  98. Serbetçi, K.; Uysal, O.; Erkasap, N.; Köken, T.; Baydemir, C.; Erkasap, S. Anti-apoptotic and antioxidant effect of leptin on CCl₄-induced acute liver injury in rats. Mol. Biol. Rep. 2012, 39, 1173–1180. [Google Scholar] [CrossRef]
  99. Li, F.; Chen, J.; Liu, Y.; Gu, Z.; Jiang, M.; Zhang, L.; Chen, S.Y.; Deng, Z.; McClain, C.J.; Feng, W. Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation. Cells 2021, 10, 3333. [Google Scholar] [CrossRef]
  100. Yasuzaki, H.; Yoshida, S.; Hashimoto, T.; Shibata, W.; Inamori, M.; Toya, Y.; Tamura, K.; Maeda, S.; Umemura, S. Involvement of the apelin receptor APJ in Fas-induced liver injury. Liver Int. 2013, 33, 118–126. [Google Scholar] [CrossRef]
  101. Garcia Whitlock, A.E.; Sostre-Colón, J.; Gavin, M.; Martin, N.D.; Baur, J.A.; Sims, C.A.; Titchenell, P.M. Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia. Mol. Metab. 2021, 51, 101246. [Google Scholar] [CrossRef] [PubMed]
  102. Begriche, K.; Massart, J.; Robin, M.A.; Borgne-Sanchez, A.; Fromenty, B. Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver. J. Hepatol. 2011, 54, 773–794. [Google Scholar] [CrossRef] [PubMed]
  103. Deng, Z.H., Jr.; Yan, G.T.; Wang, L.H.; Zhang, J.Y.; Xue, H.; Zhang, K. Leptin relieves intestinal ischemia/reperfusion injury by promoting ERK1/2 phosphorylation and the NO signaling pathway. J. Trauma Acute Care Surg. 2012, 72, 143–149. [Google Scholar] [CrossRef] [PubMed]
  104. Ikejima, K.; Honda, H.; Yoshikawa, M.; Hirose, M.; Kitamura, T.; Takei, Y.; Sato, N. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001, 34, 288–297. [Google Scholar] [CrossRef]
  105. Berezin, A.E.; Berezin, A.A.; Lichtenauer, M. Myokines and Heart Failure: Challenging Role in Adverse Cardiac Remodeling, Myopathy, and Clinical Outcomes. Dis. Markers 2021, 2021, 6644631. [Google Scholar] [CrossRef]
  106. Pang, B.P.S.; Chan, W.S.; Chan, C.B. Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle-Do Myokines Play a Role? Antioxidants 2021, 10, 179. [Google Scholar] [CrossRef]
  107. Hardie, D.G. AMP-activated protein kinase: An energy sensor that regulates all aspects of cell function. Genes Dev. 2011, 25, 1895–1908. [Google Scholar] [CrossRef][Green Version]
  108. Wu, Z.; Puigserver, P.; Andersson, U.; Zhang, C.; Adelmant, G.; Mootha, V.; Troy, A.; Cinti, S.; Lowell, B.; Scarpulla, R.C.; et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98, 115–124. [Google Scholar] [CrossRef][Green Version]
  109. Bohovych, I.; Khalimonchuk, O. Sending Out an SOS: Mitochondria as a Signaling Hub. Front. Cell Dev. Biol. 2016, 4, 109. [Google Scholar] [CrossRef][Green Version]
  110. Pan, X.; Shao, Y.; Wu, F.; Wang, Y.; Xiong, R.; Zheng, J.; Tian, H.; Wang, B.; Wang, Y.; Zhang, Y.; et al. FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice. Cell Metab. 2018, 27, 1323–1337.e5. [Google Scholar] [CrossRef][Green Version]
  111. Nagatomo, I.; Nakanishi, K.; Yamamoto, R.; Ide, S.; Ishibashi, C.; Moriyama, T.; Yamauchi-Takihara, K. Soluble angiotensin-converting enzyme 2 association with lipid metabolism. Front. Med. 2022, 9, 955928. [Google Scholar] [CrossRef]
  112. Landecho, M.F.; Tuero, C.; Valentí, V.; Bilbao, I.; de la Higuera, M.; Frühbeck, G. Relevance of Leptin and Other Adipokines in Obesity-Associated Cardiovascular Risk. Nutrients 2019, 11, 2664. [Google Scholar] [CrossRef][Green Version]
  113. Kotiadis, V.N.; Duchen, M.R.; Osellame, L.D. Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochim. Biophys. Acta 2014, 1840, 1254–1265. [Google Scholar] [CrossRef][Green Version]
  114. Musso, G.; Gambino, R.; De Michieli, F.; Durazzo, M.; Pagano, G.; Cassader, M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Hepatology 2008, 47, 1167–1177. [Google Scholar] [CrossRef]
  115. Gambino, R.; Cassader, M.; Pagano, G.; Durazzo, M.; Musso, G. Polymorphism in microsomal triglyceride transfer protein: A link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 2007, 45, 1097–1107. [Google Scholar] [CrossRef]
  116. Stasinou, E.; Argyraki, M.; Sotiriadou, F.; Lambropoulos, A.; Fotoulaki, M. Association between rs738409 and rs2896019 single-nucleotide polymorphisms of phospholipase domain-containing protein 3 and susceptibility to nonalcoholic fatty liver disease in Greek children and adolescents. Ann. Gastroenterol. 2022, 35, 297–306. [Google Scholar] [CrossRef]
  117. Zhang, R.N.; Shen, F.; Pan, Q.; Cao, H.X.; Chen, G.Y.; Fan, J.G. PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. World J. Gastroenterol. 2021, 27, 3863–3876. [Google Scholar] [CrossRef]
  118. Ali, I.I.; D’Souza, C.; Singh, J.; Adeghate, E. Adropin’s Role in Energy Homeostasis and Metabolic Disorders. Int. J. Mol. Sci. 2022, 23, 58318. [Google Scholar] [CrossRef]
  119. Kumar, K.G.; Trevaskis, J.L.; Lam, D.D.; Sutton, G.M.; Koza, R.A.; Chouljenko, V.N.; Kousoulas, K.G.; Rogers, P.M.; Kesterson, R.A.; Thearle, M.; et al. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008, 8, 468–481. [Google Scholar] [CrossRef][Green Version]
  120. Mushala, B.A.S.; Scott, I. Adropin: A hepatokine modulator of vascular function and cardiac fuel metabolism. Am. J. Physiol. Heart Circ. Physiol. 2021, 320, H238–H244. [Google Scholar] [CrossRef]
  121. Jasaszwili, M.; Billert, M.; Strowski, M.Z.; Nowak, K.W.; Skrzypski, M. Adropin as A Fat-Burning Hormone with Multiple Functions-Review of a Decade of Research. Molecules 2020, 25, 549. [Google Scholar] [CrossRef] [PubMed][Green Version]
  122. Maudsley, S.; Walter, D.; Schrauwen, C.; Van Loon, N.; Harputluoğlu, İ.; Lenaerts, J.; McDonald, P. Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process. Int. J. Mol. Sci. 2022, 23, 13598. [Google Scholar] [CrossRef] [PubMed]
  123. Kalaany, N.Y.; Mangelsdorf, D.J. LXRS and FXR: The yin and yang of cholesterol and fat metabolism. Annu. Rev. Physiol. 2006, 68, 159–191. [Google Scholar] [CrossRef] [PubMed]
  124. Yang, W.; Liu, L.; Wei, Y.; Fang, C.; Liu, S.; Zhou, F.; Li, Y.; Zhao, G.; Guo, Z.; Luo, Y.; et al. Exercise suppresses NLRP3 inflammasome activation in mice with diet-induced NASH: A plausible role of adropin. Lab. Investig. 2021, 101, 369–380. [Google Scholar] [CrossRef]
  125. Thapa, D.; Stoner, M.W.; Zhang, M.; Xie, B.; Manning, J.R.; Guimaraes, D.; Shiva, S.; Jurczak, M.J.; Scott, I. Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway. Redox Biol. 2018, 18, 25–32. [Google Scholar] [CrossRef]
  126. Lovren, F.; Pan, Y.; Quan, A.; Singh, K.K.; Shukla, P.C.; Gupta, M.; Al-Omran, M.; Teoh, H.; Verma, S. Adropin is a novel regulator of endothelial function. Circulation 2010, 122 (Suppl. 11), S185–S192. [Google Scholar] [CrossRef][Green Version]
  127. Wu, L.; Fang, J.; Yuan, X.; Xiong, C.; Chen, L. Adropin reduces hypoxia/reoxygenation-induced myocardial injury via the reperfusion injury salvage kinase pathway. Exp. Ther. Med. 2019, 18, 3307–3314. [Google Scholar] [CrossRef][Green Version]
  128. Soltani, S.; Kolahdouz-Mohammadi, R.; Aydin, S.; Yosaee, S.; Clark, C.C.T.; Abdollahi, S. Circulating levels of adropin and overweight/obesity: A systematic review and meta-analysis of observational studies. Hormones 2022, 21, 15–22. [Google Scholar] [CrossRef]
  129. Yosaee, S.; Soltani, S.; Sekhavati, E.; Jazayeri, S. Adropin—A Novel Biomarker of Heart Disease: A Systematic Review Article. Iran. J. Public Health 2016, 45, 1568–1576. [Google Scholar]
  130. Li, L.; Xie, W.; Zheng, X.L.; Yin, W.D.; Tang, C.K. A novel peptide adropin in cardiovascular diseases. Clin. Chim. Acta 2016, 453, 107–113. [Google Scholar] [CrossRef]
  131. Maciorkowska, M.; Musiałowska, D.; Małyszko, J. Adropin and irisin in arterial hypertension, diabetes mellitus and chronic kidney disease. Adv. Clin. Exp. Med. 2019, 28, 1571–1575. [Google Scholar] [CrossRef]
  132. Aydin, S.; Eren, M.N.; Yilmaz, M.; Kalayci, M.; Yardim, M.; Alatas, O.D.; Kuloglu, T.; Balaban, H.; Cakmak, T.; Kobalt, M.A.; et al. Adropin as a potential marker of enzyme-positive acute coronary syndrome. Cardiovasc. J. Afr. 2017, 28, 40–47. [Google Scholar] [CrossRef][Green Version]
  133. Liu, F.; Cui, B.; Zhao, X.; Wu, Y.; Qin, H.; Guo, Y.; Wang, H.; Lu, M.; Zhang, S.; Shen, J.; et al. Correlation of Serum Adropin Levels with Risk Factors of Cardiovascular Disease in Hemodialysis Patients. Metab. Syndr. Relat. Disord. 2021, 19, 401–408. [Google Scholar] [CrossRef]
  134. Berezin, A.A.; Obradovic, Z.; Novikov, E.V.; Boxhammer, E.; Lichtenauer, M.; Berezin, A.E. Interplay between Myokine Profile and Glycemic Control in Type 2 Diabetes Mellitus Patients with Heart Failure. Diagnostics 2022, 12, 2940. [Google Scholar] [CrossRef]
  135. Jurrissen, T.J.; Ramirez-Perez, F.I.; Cabral-Amador, F.J.; Soares, R.N.; Pettit-Mee, R.J.; Betancourt-Cortes, E.E.; McMillan, N.J.; Sharma, N.; Rocha HN, M.; Fujie, S.; et al. Role of adropin in arterial stiffening associated with obesity and type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol. 2022, 323, H879–H891. [Google Scholar] [CrossRef]
  136. Zhao, L.P.; You, T.; Chan, S.P.; Chen, J.C.; Xu, W.T. Adropin is associated with hyperhomocysteine and coronary atherosclerosis. Exp. Ther. Med. 2016, 11, 1065–1070. [Google Scholar] [CrossRef][Green Version]
  137. Chen, X.; Xue, H.; Fang, W.; Chen, K.; Chen, S.; Yang, W.; Shen, T.; Chen, X.; Zhang, P.; Ling. Adropin protects against liver injury in nonalcoholic steatohepatitis via the Nrf2 mediated antioxidant capacity. Redox Biol. 2019, 21, 101068. [Google Scholar] [CrossRef]
  138. Chen, X.; Sun, X.; Shen, T.; Chen, Q.; Chen, S.; Pang, J.; Mi, J.; Tang, Y.; You, Y.; Xu, H.; et al. Lower adropin expression is associated with oxidative stress and severity of nonalcoholic fatty liver disease. Free Radic. Biol. Med. 2020, 160, 191–198. [Google Scholar] [CrossRef]
  139. Eser Karlidag, G.; Arslan Solmaz, O. Are adropin, apelin, elabela, asprosin and betatrophin biomarkers for chronic hepatitis and staging of fibrosis? Biotech. Histochem. 2020, 95, 152–159. [Google Scholar] [CrossRef]
  140. Skrzypski, M.; Kołodziejski, P.A.; Pruszyńska-Oszmałek, E.; Wojciechowicz, T.; Janicka, P.; Krążek, M.; Małek, E.; Strowski, M.Z.; Nowak, K.W. Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile, Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum. Int. J. Mol. Sci. 2022, 23, 79807. [Google Scholar] [CrossRef]
  141. Li, Y.X.; Cheng, K.C.; Liu, I.M.; Niu, H.S. Myricetin Increases Circulating Adropin Level after Activation of Glucagon-like Peptide 1 (GLP-1) Receptor in Type-1 Diabetic Rats. Pharmaceuticals 2022, 15, 173. [Google Scholar] [CrossRef] [PubMed]
  142. Tičinović Kurir, T.; Miličević, T.; Novak, A.; Vilović, M.; Božić, J. Adropin—Potential link in cardiovascular protection for obese male type 2 diabetes mellitus patients treated with liraglutide. Acta Clin. Croat. 2020, 59, 344–350. [Google Scholar] [CrossRef] [PubMed]
  143. Mori, K.; Emoto, M.; Inaba, M. Fetuin-A: A multifunctional protein. Recent Pat. Endocr. Metab. Immune Drug Discov. 2011, 5, 124–146. [Google Scholar] [CrossRef] [PubMed]
  144. Khadir, A.; Kavalakatt, S.; Madhu, D.; Tiss, A. Fetuin-a expression profile in mouse and human adipose tissue. Lipids Health Dis. 2020, 19, 38. [Google Scholar] [CrossRef][Green Version]
  145. Meex, R.C.R.; Watt, M.J. Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance. Nat. Rev. Endocrinol. 2017, 13, 509–520. [Google Scholar] [CrossRef]
  146. Sardana, O.; Goyal, R.; Bedi, O. Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD. Inflammopharmacology 2021, 29, 1061–1074. [Google Scholar] [CrossRef]
  147. Mukhuty, A.; Fouzder, C.; Kundu, R. Fetuin-A excess expression amplifies lipid induced apoptosis and β-cell damage. J. Cell. Physiol. 2022, 237, 532–550. [Google Scholar] [CrossRef]
  148. Shen, X.; Yang, L.; Yan, S.; Zheng, H.; Liang, L.; Cai, X.; Liao, M. Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity. Mol. Cell Endocrinol. 2015, 412, 1–11. [Google Scholar] [CrossRef]
  149. Mukhuty, A.; Fouzder, C.; Kundu, R. Fetuin-A secretion from β-cells leads to accumulation of macrophages in islets, aggravates inflammation and impairs insulin secretion. J. Cell Sci. 2021, 134, jcs258507. [Google Scholar] [CrossRef]
  150. Rudloff, S.; Jahnen-Dechent, W.; Huynh-Do, U. Tissue chaperoning-the expanded functions of fetuin-A beyond inhibition of systemic calcification. Pflugers. Arch. 2022, 474, 949–962. [Google Scholar] [CrossRef]
  151. Guo, V.Y.; Cao, B.; Cai, C.; Cheng, K.K.; Cheung, B.M.Y. Fetuin-A levels and risk of type 2 diabetes mellitus: A systematic review and meta-analysis. Acta Diabetol. 2018, 55, 87–98. [Google Scholar] [CrossRef]
  152. Jirak, P.; Stechemesser, L.; Moré, E.; Franzen, M.; Topf, A.; Mirna, M.; Paar, V.; Pistulli, R.; Kretzschmar, D.; Wernly, B.; et al. Clinical implications of fetuin-A. Adv. Clin. Chem. 2019, 89, 79–130. [Google Scholar] [CrossRef]
  153. Sujana, C.; Huth, C.; Zierer, A.; Meesters, S.; Sudduth-Klinger, J.; Koenig, W.; Herder, C.; Peters, A.; Thorand, B. Association of fetuin-A with incident type 2 diabetes: Results from the MONICA/KORA Augsburg study and a systematic meta-analysis. Eur. J. Endocrinol. 2018, 178, 389–398. [Google Scholar] [CrossRef][Green Version]
  154. Yamasandhi, P.G.; Dharmalingam, M.; Balekuduru, A. Fetuin-A in newly detected type 2 diabetes mellitus as a marker of non-alcoholic fatty liver disease. Indian J. Gastroenterol. 2021, 40, 556–562. [Google Scholar] [CrossRef]
  155. Ossareh, S.; Rayatnia, M.; Vahedi, M.; Jafari, H.; Zebarjadi, M. Association of Serum Fetuin-A with Vascular Calcification in Hemodialysis Patients and Its’ Impact on 3-year Mortality. Iran. J. Kidney Dis. 2020, 14, 500–509. [Google Scholar] [PubMed]
  156. Lebensztejn, D.M.; Flisiak-Jackiewicz, M.; Białokoz-Kalinowska, I.; Bobrus-Chociej, A.; Kowalska, I. Hepatokines and non-alcoholic fatty liver disease. Acta Biochim. Pol. 2016, 63, 459–467. [Google Scholar] [CrossRef][Green Version]
  157. Kröger, J.; Meidtner, K.; Stefan, N.; Guevara, M.; Kerrison, N.D.; Ardanaz, E.; Aune, D.; Boeing, H.; Dorronsoro, M.; Dow, C.; et al. Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis. Diabetes 2018, 67, 1200–1205. [Google Scholar] [CrossRef][Green Version]
  158. Jensen, M.K.; Jensen, R.A.; Mukamal, K.J.; Guo, X.; Yao, J.; Sun, Q.; Cornelis, M.; Liu, Y.; Chen, M.H.; Kizer, J.R.; et al. Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium. Hum. Mol. Genet. 2017, 26, 2156–2163. [Google Scholar] [CrossRef][Green Version]
  159. Umapathy, D.; Subramanyam, P.V.; Krishnamoorthy, E.; Viswanathan, V.; Ramkumar, K.M. Association of Fetuin-A with Thr256Ser exon polymorphism of α2-Heremans Schmid Glycoprotein (AHSG) gene in type 2 diabetic patients with overt nephropathy. J. Diabetes Complicat. 2022, 36, 108074. [Google Scholar] [CrossRef]
  160. Von Loeffelholz, C.; Horn, P.; Birkenfeld, A.L.; Claus, R.A.; Metzing, B.U.; Döcke, S.; Jahreis, G.; Heller, R.; Hoppe, S.; Stockmann, M.; et al. Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease. J. Investig. Surg. 2016, 29, 266–274. [Google Scholar] [CrossRef]
  161. Sato, M.; Kamada, Y.; Takeda, Y.; Kida, S.; Ohara, Y.; Fujii, H.; Akita, M.; Mizutani, K.; Yoshida, Y.; Yamada, M.; et al. Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects. Liver Int. 2015, 35, 925–935. [Google Scholar] [CrossRef] [PubMed]
  162. Celebi, G.; Genc, H.; Gurel, H.; Sertoglu, E.; Kara, M.; Tapan, S.; Acikel, C.; Karslioglu, Y.; Ercin, C.N.; Dogru, T. The relationship of circulating fetuin-a with liver histology and biomarkers of systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease. Saudi J. Gastroenterol. 2015, 21, 139–145. [Google Scholar] [CrossRef] [PubMed]
  163. Toprak, K.; Görpelioğlu, S.; Özsoy, A.; Özdemir, Ş.; Ayaz, A. Does fetuin-A mediate the association between pro-inflammatory diet and type-2 diabetes mellitus risk? Nutr. Hosp. 2022, 39, 383–392. [Google Scholar] [CrossRef] [PubMed]
  164. Wang, H.; Sama, A.E. Anti-inflammatory role of fetuin-A in injury and infection. Curr. Mol. Med. 2012, 12, 625–633. [Google Scholar] [CrossRef][Green Version]
  165. Tomita, Y.; Misaka, T.; Yoshihisa, A.; Ichijo, Y.; Ishibashi, S.; Matsuda, M.; Yamadera, Y.; Ohara, H.; Sugawara, Y.; Hotsuki, Y.; et al. Decreases in hepatokine Fetuin-A levels are associated with hepatic hypoperfusion and predict cardiac outcomes in patients with heart failure. Clin. Res. Cardiol. 2022, 111, 1104–1112. [Google Scholar] [CrossRef]
  166. Åkerström, B.; Gram, M. A1M, an extravascular tissue cleaning and housekeeping protein. Free Radic. Biol. Med. 2014, 74, 274–282. [Google Scholar] [CrossRef][Green Version]
  167. Bergwik, J.; Kristiansson, A.; Allhorn, M.; Gram, M.; Åkerström, B. Structure, Functions, and Physiological Roles of the Lipocalin α1-Microglobulin (A1M). Front. Physiol. 2021, 12, 645650. [Google Scholar] [CrossRef]
  168. Shigetomi, H.; Onogi, A.; Kajiwara, H.; Yoshida, S.; Furukawa, N.; Haruta, S.; Tanase, Y.; Kanayama, S.; Noguchi, T.; Yamada, Y.; et al. Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain. Inflamm. Res. 2010, 59, 679–687. [Google Scholar] [CrossRef]
  169. Kristiansson, A.; Gram, M.; Flygare, J.; Hansson, S.R.; Åkerström, B.; Storry, J.R. The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis-Therapeutic Opportunities in Hemolytic Conditions. Int. J. Mol. Sci. 2020, 21, 97234. [Google Scholar] [CrossRef]
  170. Tyagi, S.; Salier, J.P.; Lal, S.K. The liver-specific human alpha(1)-microglobulin/bikunin precursor (AMBP) is capable of self-association. Arch. Biochem. Biophys. 2002, 399, 66–72. [Google Scholar] [CrossRef]
  171. Akerström, B.; Lögdberg, L.; Berggård, T.; Osmark, P.; Lindqvist, A. alpha(1)-Microglobulin: A yellow-brown lipocalin. Biochim. Biophys. Acta 2000, 1482, 172–184. [Google Scholar] [CrossRef]
  172. Rutardottir, S.; Nilsson, E.J.; Pallon, J.; Gram, M.; Åkerström, B. The cysteine 34 residue of A1M/α1-microglobulin is essential for protection of irradiated cell cultures and reduction of carbonyl groups. Free Radic. Res. 2013, 47, 541–550. [Google Scholar] [CrossRef][Green Version]
  173. Bergwik, J.; Kristiansson, A.; Welinder, C.; Göransson, O.; Hansson, S.R.; Gram, M.; Erlandsson, L.; Åkerström, B. Knockout of the radical scavenger α1-microglobulin in mice results in defective bikunin synthesis, endoplasmic reticulum stress and increased body weight. Free Radic. Biol. Med. 2021, 162, 160–170. [Google Scholar] [CrossRef]
  174. Kristiansson, A.; Ahlstedt, J.; Holmqvist, B.; Brinte, A.; Tran, T.A.; Forssell-Aronsson, E.; Strand, S.E.; Gram, M.; Åkerström, B. Protection of Kidney Function with Human Antioxidation Protein α1-Microglobulin in a Mouse 177Lu-DOTATATE Radiation Therapy Model. Antioxid. Redox Signal. 2019, 30, 1746–1759. [Google Scholar] [CrossRef][Green Version]
  175. Kristiansson, A.; Örbom, A.; Timmermand, O.V.; Ahlstedt, J.; Strand, S.E.; Åkerström, B. Kidney Protection with the Radical Scavenger α1-Microglobulin (A1M) during Peptide Receptor Radionuclide and Radioligand Therapy. Antioxidants 2021, 10, 81271. [Google Scholar] [CrossRef]
  176. Cederlund, M.; Deronic, A.; Pallon, J.; Sørensen, O.E.; Åkerström, B. A1M/α1-microglobulin is proteolytically activated by myeloperoxidase, binds its heme group and inhibits low density lipoprotein oxidation. Front. Physiol. 2015, 6, 11. [Google Scholar] [CrossRef][Green Version]
  177. Fukao, Y.; Nagasawa, H.; Nihei, Y.; Hiki, M.; Naito, T.; Kihara, M.; Gohda, T.; Ueda, S.; Suzuki, Y. COVID-19-induced acute renal tubular injury associated with elevation of serum inflammatory cytokine. Clin. Exp. Nephrol. 2021, 25, 1240–1246. [Google Scholar] [CrossRef]
  178. Tang, J.; Shi, Y.; Deng, R.; Zhang, J.; An, Y.; Li, Y.; Wang, L. Cytokine Profile in Calcineurin Inhibitor-Induced Chronic Nephrotoxicity in Chinese Liver Transplant Recipients. Transplant. Proc. 2016, 48, 2756–2762. [Google Scholar] [CrossRef]
  179. Fisher, F.M.; Maratos-Flier, E. Understanding the Physiology of FGF21. Annu. Rev. Physiol. 2016, 78, 223–241. [Google Scholar] [CrossRef][Green Version]
  180. Cuevas-Ramos, D.; Aguilar-Salinas, C.A. Modulation of energy balance by fibroblast growth factor 21. Horm. Mol. Biol. Clin. Investig. 2016, 30. [Google Scholar] [CrossRef]
  181. Giralt, M.; Gavaldà-Navarro, A.; Villarroya, F. Fibroblast growth factor-21, energy balance and obesity. Mol. Cell. Endocrinol. 2015, 418 Pt 1, 66–73. [Google Scholar] [CrossRef] [PubMed]
  182. Geng, L.; Lam, K.S.L.; Xu, A. The therapeutic potential of FGF21 in metabolic diseases: From bench to clinic. Nat. Rev. Endocrinol. 2020, 16, 654–667. [Google Scholar] [CrossRef] [PubMed]
  183. Byun, S.; Seok, S.; Kim, Y.C.; Zhang, Y.; Yau, P.; Iwamori, N.; Xu, H.E.; Ma, J.; Kemper, B.; Kemper, J.K. Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase. Nat. Commun. 2020, 11, 807. [Google Scholar] [CrossRef] [PubMed][Green Version]
  184. Zarei, M.; Pizarro-Delgado, J.; Barroso, E.; Palomer, X.; Vázquez-Carrera, M. Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis. Trends. Pharmacol. Sci. 2020, 41, 199–208. [Google Scholar] [CrossRef]
  185. Zhang, Y.; Liu, D.; Long, X.X.; Fang, Q.C.; Jia, W.P.; Li, H.T. The role of FGF21 in the pathogenesis of cardiovascular disease. Chin. Med. J. 2021, 134, 2931–2943. [Google Scholar] [CrossRef]
  186. Yang, X.; Jin, Z.; Lin, D.; Shen, T.; Zhang, J.; Li, D.; Wang, X.; Zhang, C.; Lin, Z.; Li, X.; et al. FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway. J. Cell. Mol. Med. 2022, 26, 868–879. [Google Scholar] [CrossRef]
  187. Zhang, J.; Cheng, Y.; Gu, J.; Wang, S.; Zhou, S.; Wang, Y.; Tan, Y.; Feng, W.; Fu, Y.; Mellen, N.; et al. Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice. Clin. Sci. 2016, 130, 625–641. [Google Scholar] [CrossRef]
  188. Li, Y.; Wong, K.; Giles, A.; Jiang, J.; Lee, J.W.; Adams, A.C.; Kharitonenkov, A.; Yang, Q.; Gao, B.; Guarente, L.; et al. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 2014, 146, 539–549.e7. [Google Scholar] [CrossRef]
  189. Wu, A.; Feng, B.; Yu, J.; Yan, L.; Che, L.; Zhuo, Y.; Luo, Y.; Yu, B.; Wu, D.; Chen, D. Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis. Redox Biol. 2021, 46, 102131. [Google Scholar] [CrossRef]
  190. Wu, L.; Mo, W.; Feng, J.; Li, J.; Yu, Q.; Li, S.; Zhang, J.; Chen, K.; Ji, J.; Dai, W.; et al. Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non-alcoholic fatty liver disease by up-regulating the FGF21/PGC-1α pathway. Br. J. Pharmacol. 2020, 177, 3760–3777. [Google Scholar] [CrossRef]
  191. Prida, E.; Álvarez-Delgado, S.; Pérez-Lois, R.; Soto-Tielas, M.; Estany-Gestal, A.; Fernø, J.; Seoane, L.M.; Quiñones, M.; Al-Massadi, O. Liver Brain Interactions: Focus on FGF21 a Systematic Review. Int. J. Mol. Sci. 2022, 23, 13318. [Google Scholar] [CrossRef]
  192. Abu-Odeh, M.; Zhang, Y.; Reilly, S.M.; Ebadat, N.; Keinan, O.; Valentine, J.M.; Hafezi-Bakhtiari, M.; Ashayer, H.; Mamoun, L.; Zhou, X.; et al. FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes. Cell Rep. 2021, 35, 109331. [Google Scholar] [CrossRef]
  193. Lin, Z.; Tian, H.; Lam, K.S.; Lin, S.; Hoo, R.C.; Konishi, M.; Itoh, N.; Wang, Y.; Bornstein, S.R.; Xu, A.; et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013, 17, 779–789. [Google Scholar] [CrossRef][Green Version]
  194. Takamura, T. Hepatokine Selenoprotein P-Mediated Reductive Stress Causes Resistance to Intracellular Signal Transduction. Antioxid. Redox Signal. 2020, 33, 517–524. [Google Scholar] [CrossRef]
  195. Arora, A.S.; Gores, G.J. The role of metals in ischemia/reperfusion injury of the liver. Semin. Liver Dis. 1996, 16, 31–38. [Google Scholar] [CrossRef]
  196. Saito, Y. Selenoprotein P as an in vivo redox regulator: Disorders related to its deficiency and excess. J. Clin. Biochem. Nutr. 2020, 66, 1–7. [Google Scholar] [CrossRef][Green Version]
  197. Saito, Y. Selenoprotein P as a significant regulator of pancreatic β cell function. J. Biochem. 2020, 167, 119–124. [Google Scholar] [CrossRef] [PubMed]
  198. Saito, Y. Selenium Transport Mechanism via Selenoprotein P-Its Physiological Role and Related Diseases. Front. Nutr. 2021, 8, 685517. [Google Scholar] [CrossRef]
  199. Hill, K.E.; Chittum, H.S.; Lyons, P.R.; Boeglin, M.E.; Burk, R.F. Effect of selenium on selenoprotein P expression in cultured liver cells. Biochim. Biophys. Acta 1996, 1313, 29–34. [Google Scholar] [CrossRef][Green Version]
  200. Chadani, H.; Usui, S.; Inoue, O.; Kusayama, T.; Takashima, S.I.; Kato, T.; Murai, H.; Furusho, H.; Nomura, A.; Misu, H.; et al. Endogenous Selenoprotein, P, a Liver-Derived Secretory Protein, Mediates Myocardial Ischemia/Reperfusion Injury in Mice. Int. J. Mol. Sci. 2018, 19, 30878. [Google Scholar] [CrossRef][Green Version]
  201. Caviglia, G.P.; Rosso, C.; Armandi, A.; Gaggini, M.; Carli, F.; Abate, M.L.; Olivero, A.; Ribaldone, D.G.; Saracco, G.M.; Gastaldelli, A.; et al. Interplay between Oxidative Stress and Metabolic Derangements in Non-Alcoholic Fatty Liver Disease: The Role of Selenoprotein P. Int. J. Mol. Sci. 2020, 21, 28838. [Google Scholar] [CrossRef] [PubMed]
  202. Polyzos, S.A.; Kountouras, J.; Mavrouli, M.; Katsinelos, P.; Doulberis, M.; Gavana, E.; Duntas, L. Selenoprotein P in Patients with Nonalcoholic Fatty Liver Disease. Exp. Clin. Endocrinol. Diabetes 2019, 127, 598–602. [Google Scholar] [CrossRef] [PubMed]
  203. Takeishi, R.; Misaka, T.; Ichijo, Y.; Ishibashi, S.; Matsuda, M.; Yamadera, Y.; Ohara, H.; Sugawara, Y.; Hotsuki, Y.; Watanabe, K.; et al. Increases in Hepatokine Selenoprotein P Levels Are Associated with Hepatic Hypoperfusion and Predict Adverse Prognosis in Patients with Heart Failure. J. Am. Heart Assoc. 2022, 11, e024901. [Google Scholar] [CrossRef] [PubMed]
  204. Zhang, Z.; Guo, Y.; Qiu, C.; Deng, G.; Guo, M. Protective Action of Se-Supplement Against Acute Alcoholism Is Regulated by Selenoprotein P (SelP) in the Liver. Biol. Trace Elem. Res. 2017, 175, 375–387. [Google Scholar] [CrossRef] [PubMed]
  205. di Giuseppe, R.; Koch, M.; Schlesinger, S.; Borggrefe, J.; Both, M.; Müller, H.P.; Kassubek, J.; Jacobs, G.; Nöthlings, U.; Lieb, W. Circulating selenoprotein P levels in relation to MRI-derived body fat volumes, liver fat content, and metabolic disorders. Obesity 2017, 25, 1128–1135. [Google Scholar] [CrossRef][Green Version]
  206. di Giuseppe, R.; Plachta-Danielzik, S.; Koch, M.; Nöthlings, U.; Schlesinger, S.; Borggrefe, J.; Both, M.; Müller, H.P.; Kassubek, J.; Jacobs, G.; et al. Dietary pattern associated with selenoprotein P and MRI-derived body fat volumes, liver signal intensity, and metabolic disorders. Eur. J. Nutr. 2019, 58, 1067–1079. [Google Scholar] [CrossRef]
  207. Pendyal, A.; Gelow, J.M. Cardiohepatic Interactions: Implications for Management in Advanced Heart Failure. Heart Fail. Clin. 2016, 12, 349–361. [Google Scholar] [CrossRef]
  208. Verbeeck, R.K. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur. J. Clin. Pharmacol. 2008, 64, 1147–1161. [Google Scholar] [CrossRef]
  209. Mangoni, A.A.; Jarmuzewska, E.A. The influence of heart failure on the pharmacokinetics of cardiovascular and non-cardiovascular drugs: A critical appraisal of the evidence. Br. J. Clin. Pharmacol. 2019, 85, 20–36. [Google Scholar] [CrossRef]
  210. Berezin, A.A.; Obradovic, Z.; Fushtey, I.M.; Berezina, T.A.; Novikov, E.V.; Schmidbauer, L.; Lichtenauer, M.; Berezin, A.E. The Impact of SGLT2 Inhibitor Dapagliflozin on Adropin Serum Levels in Men and Women with Type 2 Diabetes Mellitus and Chronic Heart Failure. Biomedicines 2023, 11, 457. [Google Scholar] [CrossRef]
Figure 1. Most common underlying mechanisms of the pathogenesis of cardiac hepatopathy.
Figure 1. Most common underlying mechanisms of the pathogenesis of cardiac hepatopathy.
Antioxidants 12 00516 g001
Table 1. Local and systemic effects of hepatokines involved in the pathogenesis of cardiac hepatopathy.
Table 1. Local and systemic effects of hepatokines involved in the pathogenesis of cardiac hepatopathy.
HepatokinesLocal Liver EffectSystemic EffectsReferences
Adropin↓ activation of hepatic stellate cells, ↓NLRP3 inflammasome, ↓ inflammatory gene expression, ↓ oxidative stress, ↓ lipid peroxidation, ↓ lipid toxicity, ↓ liver injury and fibrosis, ↓ autophagy, ↑ glucose metabolism, ↑ insulin sensitivity, ↑ anti-apoptotic and antioxidant effects, ↑ pre-conditioning↓ adverse cardiac remodeling, ↓ systemic inflammatory reaction, ↑ vascular integrity/endothelial function, ↑ renal and splanchnic blood flow, ↑ angiogenesis, ↑ NO production[118,122,125,126,138,139,140,141,142]
Fetuin-A↓ liver inflammation, injury and fibrosis, ↓ necrosis and apoptosis, ↓ fasting glucose levels, ↑ mitochondrial function, ↑ lipid metabolism, ↑ angiogenesis↑ antioxidant capacity, ↑ endothelial function, ↓ WAT dysfunction, ↓ inflammation, ↓ pancreatic beta-cell damage/apoptosis, ↓ adverse cardiac remodeling, ↓ vessel calcification, ↑ skeletal muscle energy metabolism, ↑ NO production[144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165]
Alpha1-microglobulinAnti-oxidative effects, ↓ apoptosis, ↓ mitochondrial damage, ↓ autophagy, ↓ hepatocyte damage, ↓ activation of hepatic stellate cells,↓ cardiac, lung and kidney injury, ↑ anti-ischemic protection[170,171,172,173,174,175,176,177,178]
Fibroblast growth factor-21↓ mitochondrial oxidative stress, ↓ autophagy, ↓ fasting glucose levels, ↑ gluconeogenesis, ↑ insulin sensitivity↓ WAT inflammation, ↓ lipolysis in WAT, ↓ fibrosis in myocardium, ↑ endothelial function, ↓ microvascular inflammation, ↑ NO production[179,180,181,182,183,184,185,186,187,188,189,190,191,192,193]
Selenoprotein P↓ oxidative stress, ↓ lipid peroxidation, ↓ lipid toxicity, ↓ liver injury and fibrosis↓ pancreatic beta-cell apoptosis, ↑ antioxidant capacity, ↑ angiogenesis, ↑ insulin sensitivity[194,195,196,197,198,199,200,201,202,203,204,205,206]
Notes: ↓, decrease; ↑, increase. Abbreviations: WAT, white adipose tissue; NO, nitric oxide.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Berezin, A.A.; Obradovic, Z.; Berezina, T.A.; Boxhammer, E.; Lichtenauer, M.; Berezin, A.E. Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines. Antioxidants 2023, 12, 516.

AMA Style

Berezin AA, Obradovic Z, Berezina TA, Boxhammer E, Lichtenauer M, Berezin AE. Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines. Antioxidants. 2023; 12(2):516.

Chicago/Turabian Style

Berezin, Alexander A., Zeljko Obradovic, Tetiana A. Berezina, Elke Boxhammer, Michael Lichtenauer, and Alexander E. Berezin. 2023. "Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines" Antioxidants 12, no. 2: 516.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop