Editorial

3 pages, 170 KiB

Open AccessEditorial

NAFLD: From Mechanisms to Therapeutic Approaches

by Karim Gariani and François R. Jornayvaz

Biomedicines 2022, 10(7), 1747; https://doi.org/10.3390/biomedicines10071747 - 20 Jul 2022

Cited by 2 | Viewed by 1255

Nonalcoholic fatty liver disease (NAFLD) now represents the most frequent chronic liver disease worldwide [...] Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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19 pages, 2516 KiB

Open AccessArticle

Rifaximin Improves Spatial Learning and Memory Impairment in Rats with Liver Damage-Associated Neuroinflammation

by Paola Leone, Gergana Mincheva, Tiziano Balzano, Michele Malaguarnera, Vicente Felipo and Marta Llansola

Biomedicines 2022, 10(6), 1263; https://doi.org/10.3390/biomedicines10061263 - 28 May 2022

Cited by 12 | Viewed by 2287

Abstract

Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, [...] Read more.

Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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12 pages, 3751 KiB

Open AccessArticle

Mechanisms Underlying Antipsychotic-Induced NAFLD and Iron Dysregulation: A Multi-Omic Approach

by Meghan May, Deborah Barlow, Radwa Ibrahim and Karen L. Houseknecht

Biomedicines 2022, 10(6), 1225; https://doi.org/10.3390/biomedicines10061225 - 24 May 2022

Cited by 5 | Viewed by 4050

Abstract

Atypical antipsychotic (AA) medications are widely prescribed for the treatment of psychiatric disorders, including schizophrenia, bipolar disorder and treatment-resistant depression. AA are associated with myriad metabolic and endocrine side effects, including systemic inflammation, weight gain, dyslipidemia and insulin resistance, all of which are [...] Read more.

Atypical antipsychotic (AA) medications are widely prescribed for the treatment of psychiatric disorders, including schizophrenia, bipolar disorder and treatment-resistant depression. AA are associated with myriad metabolic and endocrine side effects, including systemic inflammation, weight gain, dyslipidemia and insulin resistance, all of which are associated with increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is highly prevalent in patients with mental illness, and AA have been shown to increase incidence of NAFLD pre-clinically and clinically. However, the underlying mechanisms have not been described. We mined multi-omic datasets from preclinical murine models of sub-chronic risperidone or olanzapine treatment, in vitro exposure of human cells to risperidone and psychiatric patients following onset of aripiprazole therapy focused on pathways associated with the pathophysiology of NAFLD, including iron accumulation, systemic inflammation and dyslipidemia. We identified numerous differentially expressed traits affecting these pathways conserved across study systems and AA medications. We used these findings to propose mechanisms for AA-associated development of NAFLD and dysregulated iron homeostasis. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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11 pages, 2473 KiB

Open AccessArticle

Empagliflozin Reduces the Progression of Hepatic Fibrosis in a Mouse Model and Inhibits the Activation of Hepatic Stellate Cells via the Hippo Signalling Pathway

by Yu-Jung Heo, Nami Lee, Sung-E Choi, Ja-Young Jeon, Seung-Jin Han, Dae-Jung Kim, Yup Kang, Kwan-Woo Lee and Hae-Jin Kim

Biomedicines 2022, 10(5), 1032; https://doi.org/10.3390/biomedicines10051032 - 29 Apr 2022

Cited by 7 | Viewed by 2076

Abstract

Hepatic fibrosis is the excessive production and deposition of the extracellular matrix, resulting in the activation of the fibrogenic phenotype of hepatic stellate cells (HSCs). The Hippo/Yes-associated protein (YAP) signalling pathway is a highly conserved kinase cascade that is critical in regulating cell [...] Read more.

Hepatic fibrosis is the excessive production and deposition of the extracellular matrix, resulting in the activation of the fibrogenic phenotype of hepatic stellate cells (HSCs). The Hippo/Yes-associated protein (YAP) signalling pathway is a highly conserved kinase cascade that is critical in regulating cell proliferation, differentiation, and survival, and controls stellate cell activation. Empagliflozin, a sodium-glucose cotransporter type-2 inhibitor, is an antidiabetic drug that may prevent fibrotic progression by reducing hepatic steatosis and inflammation. However, little is known about its mechanism of action in liver fibrosis. In this study, we used male C57 BL/6 J mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) as a model for hepatic fibrosis. For 5 weeks, the mice received either a vehicle or empagliflozin based on their assigned group. Empagliflozin attenuated CDAHFD-induced liver fibrosis. Thereafter, we identified the Hippo pathway, along with its effector, YAP, as a key pathway in the mouse liver. Hippo signalling is inactivated in the fibrotic liver, but empagliflozin treatment activated Hippo signalling and decreased YAP activity. In addition, empagliflozin downregulated the expression of pro-fibrogenic genes and activated Hippo signalling in HSCs. We identified a mechanism by which empagliflozin ameliorates liver fibrosis. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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16 pages, 5437 KiB

Open AccessArticle

Comparative Transcriptome Analysis Reveals That Exendin-4 Improves Steatosis in HepG2 Cells by Modulating Signaling Pathways Related to Lipid Metabolism

by Khaoula Errafii, Olfa Khalifa, Neyla S. Al-Akl and Abdelilah Arredouani

Biomedicines 2022, 10(5), 1020; https://doi.org/10.3390/biomedicines10051020 - 28 Apr 2022

Cited by 5 | Viewed by 2037

Abstract

No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a [...] Read more.

No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a cell model of steatosis to overcome pleiotropy. We treated steatotic HepG2 cells with the GLP-1RA Exendin-4 (Ex-4). We compared the transcriptome profiles of untreated steatotic, and Ex-4-treated steatotic cells, and used Ingenuity Pathway Analysis (IPA) to identify the signaling pathways and associated genes involved in the protective effect of Ex-4. Ex-4 treatment significantly reduces steatosis. RNA-seq analysis revealed 209 differentially expressed genes (DEGs) between steatotic and untreated cells, with farnesoid X receptor/retinoid X receptor (FXR/RXR) (p = 8.9 × 10⁻⁷) activation being the top regulated canonical pathway identified by IPA. Furthermore, 1644 DEGs were identified between steatotic cells and Ex-4-treated cells, with liver X receptor/retinoid X receptor (LXR/RXR) (p = 2.02 × 10⁻⁷) and FXR/RXR (p = 3.28 × 10⁻⁷) activation being the two top canonical pathways. The top molecular and cellular functions between untreated and steatotic cells were lipid metabolism, molecular transport, and small molecular biochemistry, while organismal injury and abnormalities, endocrine system disorders, and gastrointestinal disease were the top three molecular and cellular functions between Ex-4-treated and steatotic cells. Genes overlapping steatotic cells and Ex-4-treated cells were associated with several lipid metabolism processes. Unique transcriptomic differences exist between steatotic cells and Ex-4-treated steatotic cells, providing an important resource for understanding the mechanisms that underpin the protective effect of GLP-1RAs on NAFLD and for the identification of novel therapeutic targets for NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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12 pages, 604 KiB

Open AccessArticle

Hepatic Steatosis Is Associated with High White Blood Cell and Platelet Counts

by Yu-Lin Chao, Pei-Yu Wu, Jiun-Chi Huang, Yi-Wen Chiu, Jia-Jung Lee, Szu-Chia Chen, Jer-Ming Chang, Shang-Jyh Hwang and Hung-Chun Chen

Biomedicines 2022, 10(4), 892; https://doi.org/10.3390/biomedicines10040892 - 13 Apr 2022

Cited by 6 | Viewed by 3271

Abstract

The incidence of hepatic steatosis is increasing globally, and it is important to identify those at risk to prevent comorbidities. Complete blood count is a simple, convenient, and inexpensive laboratory examination which can be used to obtain white blood cell (WBC) and platelet [...] Read more.

The incidence of hepatic steatosis is increasing globally, and it is important to identify those at risk to prevent comorbidities. Complete blood count is a simple, convenient, and inexpensive laboratory examination which can be used to obtain white blood cell (WBC) and platelet counts. The aims of this study were to investigate the relationships between WBC and platelet counts with hepatic steatosis, and whether WBC and platelet counts were associated with the severity of hepatic steatosis. We enrolled 1969 participants residing in southern Taiwan who took part in a health survey from June 2016 to September 2018 in this cross-sectional study. None of the participants were heavy alcohol users or had a history of hepatitis B or C. We collected laboratory data, and the severity of hepatic steatosis was determined by abdominal ultrasound. The overall prevalence rate of hepatic steatosis was 42.0%. There were significant trends of stepwise increases in WBC count (p < 0.001) corresponding to the severity of hepatic steatosis. After multivariable linear regression analysis, hepatic steatosis was significantly associated with high WBC count (coefficient β, 0.209; 95% confidence interval (CI), 0.055 to 0.364; p = 0.008) and high platelet count (coefficient β, 12.213; 95% CI, 6.092 to 18.334; p < 0.001); also, higher WBC counts corresponded with the severity of hepatic steatosis. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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14 pages, 2899 KiB

Open AccessArticle

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

by Abhishek Kulkarni, Sara Ibrahim, Isra Haider, Amina Basha, Emma Montgomery, Ebru Ermis, Raghavendra G. Mirmira and Ryan M. Anderson

Biomedicines 2022, 10(2), 479; https://doi.org/10.3390/biomedicines10020479 - 17 Feb 2022

Cited by 8 | Viewed by 3996

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory cytokines following induction with doxycycline (second hit). These hits promoted fat accumulation and liver inflammation, as demonstrated by the high expression of inflammatory cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with pioglitazone, a drug shown to be beneficial for NAFLD in humans, and measured a sharp reduction in liver lipid accumulation. These results demonstrate new utility for zebrafish in modeling early NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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21 pages, 33854 KiB

Open AccessArticle

The Concept of Indeterminable NASH Inducted by Preoperative Diet and Metabolic Surgery: Analyses of Histopathological and Clinical Features

by Akira Sasaki, Akira Umemura, Kazuyuki Ishida, Naoto Takahashi, Haruka Nikai, Hiroyuki Nitta, Yasuhiro Takikawa, Keisuke Kakisaka, Tamami Abe, Masao Nishiya and Tamotsu Sugai

Biomedicines 2022, 10(2), 453; https://doi.org/10.3390/biomedicines10020453 - 15 Feb 2022

Cited by 2 | Viewed by 2317

Abstract

Practitioners routinely perform intraoperative liver biopsies during laparoscopic sleeve gastrectomy (LSG) to evaluate nonalcoholic fatty liver disease (NAFLD). In some patients, hepatocyte ballooning, inflammation, and fibrosis without steatosis are observed, even in the absence of other etiologies. We call this finding indeterminable nonalcoholic [...] Read more.

Practitioners routinely perform intraoperative liver biopsies during laparoscopic sleeve gastrectomy (LSG) to evaluate nonalcoholic fatty liver disease (NAFLD). In some patients, hepatocyte ballooning, inflammation, and fibrosis without steatosis are observed, even in the absence of other etiologies. We call this finding indeterminable nonalcoholic steatohepatitis (Ind-NASH). In this study, we clarified the prevalence, as well as histopathological and clinical features, of Ind-NASH through intraoperative liver biopsy in Japanese patients presenting with severe obesity. We enrolled 63 patients who had undergone LSG and intraoperative liver biopsy. In patients diagnosed with histopathological NASH, we performed protocol liver biopsies at 6 and 12 months after LSG. We statistically analyzed these histopathological findings and clinical parameters and found the prevalence rate of Ind-NASH discovered through intraoperative biopsy to be 15.9%. Protocol liver biopsy also revealed that Ind-NASH was an intermediate condition between NASH and normal liver. The clinical features of patients with Ind-NASH are a higher body weight compared to NASH (134.9 kg vs. 114.7 kg; p = 0.0245), stronger insulin resistance compared to nonalcoholic fatty liver (homeostasis model assessment–insulin resistance: 7.1 vs. 4.9; p = 0.0188), and mild liver dysfunction compared to NASH. Patients with Ind-NASH observed positive weight-loss effects from a preoperative diet compared to the postoperative course (percentage total weight loss: 32.0% vs. 26.7%; p < 0.0001). Patients with Ind-NASH may also be good candidates for metabolic surgery owing to their good treatment response; therefore, efforts should be made by specialists in the near future to deeply discuss and define Ind-NASH. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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10 pages, 547 KiB

Open AccessArticle

Prevalence of Pruritus and Association with Anxiety and Depression in Patients with Nonalcoholic Fatty Liver Disease

by Albrecht Boehlig, Florian Gerhardt, David Petroff, Florian van Boemmel, Thomas Berg, Valentin Blank, Thomas Karlas and Johannes Wiegand

Biomedicines 2022, 10(2), 451; https://doi.org/10.3390/biomedicines10020451 - 15 Feb 2022

Cited by 4 | Viewed by 2216

Abstract

Patient-reported outcomes are important in nonalcoholic fatty liver disease (NAFLD). Pruritus is of special interest for evolving therapies with farnesoid X receptor (FXR) agonists. The aim of this study was to investigate the prevalence of pruritus in a real-life NAFLD cohort and analyze [...] Read more.

Patient-reported outcomes are important in nonalcoholic fatty liver disease (NAFLD). Pruritus is of special interest for evolving therapies with farnesoid X receptor (FXR) agonists. The aim of this study was to investigate the prevalence of pruritus in a real-life NAFLD cohort and analyze associations with anxiety and depression. Pruritus was assessed using a visual analogue- (VAS) and 5-D itch-scale (5-D). Anxiety and depression were evaluated by Beck’s-Depression-Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS-A, HADS-D). An optimal logistic regression model was found with a stepwise procedure to investigate variables associated with pruritus. In total, 123 NAFLD patients were recruited. VAS and 5-D were highly correlated (Spearman’s correlation coefficient 0.89). Moderate/severe pruritus was reported in 19% (VAS) and 21% (5-D) of patients. Anxiety and depression were present in 12% and 4% (HADS-A and HADS-D, respectively) and 12% (BDI) of cases. There was a significant association between VAS and BDI (p = 0.019). The final multivariate model for 5-D included diabetes mellitus (OR 4.51; p = 0.01), BDI (OR 5.98; p = 0.024), and HADS-A (OR 7.75; p = 0.011). One-fifth of NAFLD patients reported moderate or severe pruritus. 5-D was significantly associated with diabetes mellitus, depression, and anxiety. These findings should be tested in larger populations and considered in candidates for treatment with FXR agonists. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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19 pages, 5881 KiB

Open AccessArticle

Impact of Maternal Obesity on Liver Disease in the Offspring: A Comprehensive Transcriptomic Analysis and Confirmation of Results in a Murine Model

by Beat Moeckli, Vaihere Delaune, Julien Prados, Matthieu Tihy, Andrea Peloso, Graziano Oldani, Thomas Delmi, Florence Slits, Quentin Gex, Laura Rubbia-Brandt, Nicolas Goossens, Stéphanie Lacotte and Christian Toso

Biomedicines 2022, 10(2), 294; https://doi.org/10.3390/biomedicines10020294 - 27 Jan 2022

Cited by 6 | Viewed by 3024

Abstract

The global obesity epidemic particularly affects women of reproductive age. Offspring of obese mothers suffer from an increased risk of liver disease but the molecular mechanisms involved remain unknown. We performed an integrative genomic analysis of datasets that investigated the impact of maternal [...] Read more.

The global obesity epidemic particularly affects women of reproductive age. Offspring of obese mothers suffer from an increased risk of liver disease but the molecular mechanisms involved remain unknown. We performed an integrative genomic analysis of datasets that investigated the impact of maternal obesity on the hepatic gene expression profile of the offspring in mice. Furthermore, we developed a murine model of maternal obesity and studied the development of liver disease and the gene expression profile of the top dysregulated genes by quantitative real-time polymerase chain reaction (qPCR). Our data are available for interactive exploration on our companion webpage. We identified five publicly available datasets relevant to our research question. Pathways involved in metabolism, the innate immune system, the clotting cascade, and the cell cycle were consistently dysregulated in the offspring of obese mothers. Concerning genes involved in the development of liver disease, Egfr, Vegfb, Wnt2,Pparg and six other genes were dysregulated in multiple independent datasets. In our own model, we observed a higher tendency towards the development of non-alcoholic liver disease (60 vs. 20%) and higher levels of alanine aminotransferase (41.0 vs. 12.5 IU/l, p = 0.008) in female offspring of obese mothers. Male offspring presented higher levels of liver fibrosis (2.4 vs. 0.6% relative surface area, p = 0.045). In a qPCR gene expression analysis of our own samples, we found Fgf21, Pparg, Ppard, and Casp6 to be dysregulated by maternal obesity. Maternal obesity represents a looming threat to the liver health of future generations. Our comprehensive transcriptomic analysis will help to better understand the mechanisms of the development of liver disease in the offspring of obese mothers and can give rise to further explorations. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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16 pages, 1987 KiB

Open AccessEditor’s ChoiceArticle

Selective Isolation of Liver-Derived Extracellular Vesicles Redefines Performance of miRNA Biomarkers for Non-Alcoholic Fatty Liver Disease

by Lauren A. Newman, Zivile Useckaite, Jillian Johnson, Michael J. Sorich, Ashley M. Hopkins and Andrew Rowland

Biomedicines 2022, 10(1), 195; https://doi.org/10.3390/biomedicines10010195 - 17 Jan 2022

Cited by 27 | Viewed by 4103

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Definitive diagnosis of the progressive form, non-alcoholic steatohepatitis (NASH), requires liver biopsy, which is highly invasive and unsuited to early disease or tracking changes. Inadequate performance of current minimally invasive tools [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Definitive diagnosis of the progressive form, non-alcoholic steatohepatitis (NASH), requires liver biopsy, which is highly invasive and unsuited to early disease or tracking changes. Inadequate performance of current minimally invasive tools is a critical barrier to managing NAFLD burden. Altered circulating miRNA profiles show potential for minimally invasive tracking of NAFLD. The selective isolation of the circulating extracellular vesicle subset that originates from hepatocytes presents an important opportunity for improving the performance of miRNA biomarkers of liver disease. The expressions of miR-122, -192, and -128-3p were quantified in total cell-free RNA, global EVs, and liver-specific EVs from control, NAFL, and NASH subjects. In ASGR1+ EVs, each miR biomarker trended positively with disease severity and expression was significantly higher in NASH subjects compared with controls. The c-statistic defining the performance of ASGR1+ EV derived miRNAs was invariably >0.78. This trend was not observed in the alternative sources. This study demonstrates the capacity for liver-specific isolation to transform the performance of EV-derived miRNA biomarkers for NAFLD, robustly distinguishing patients with NAFL and NASH. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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17 pages, 4972 KiB

Open AccessArticle

Bifidobacterium bifidum Shows More Diversified Ways of Relieving Non-Alcoholic Fatty Liver Compared with Bifidobacterium adolescentis

by Linlin Wang, Ting Jiao, Qiangqing Yu, Jialiang Wang, Luyao Wang, Gang Wang, Hao Zhang, Jianxin Zhao and Wei Chen

Biomedicines 2022, 10(1), 84; https://doi.org/10.3390/biomedicines10010084 - 31 Dec 2021

Cited by 14 | Viewed by 2285

Abstract

The occurrence of non-alcoholic fatty liver disease (NAFLD) is closely related to intestinal microbiota disturbance, and probiotics has become a new strategy to assist in alleviating NAFLD. In order to investigate the effect of Bifidobacterium on NAFLD and the possible pathway, a NAFLD [...] Read more.

The occurrence of non-alcoholic fatty liver disease (NAFLD) is closely related to intestinal microbiota disturbance, and probiotics has become a new strategy to assist in alleviating NAFLD. In order to investigate the effect of Bifidobacterium on NAFLD and the possible pathway, a NAFLD model was established by using a high-fat diet (HFD) for 18 weeks. Fourteen strains of Bifidobacterium were selected (seven Bifidobacterium adolescentis and seven Bifidobacterium bifidum) for intervention. The effects of different bifidobacteria on NAFLD were evaluated from liver cell injury, liver fat deposition, liver inflammatory state and liver histopathology, and were taken as entry points to explore the mitigation approaches of bifidobacteria through energy intake, lipid metabolism, glucose metabolism and intestinal permeability. The results showed that Bifidobacterium exerts species-specific effects on NAFLD. B. bifidum exerted these effects mainly through regulating the intestinal microbiota, increasing the relative abundance of Faecalibaculum and Lactobacillus, decreasing the relative abundance of Tyzzerella, Escherichia-Shigella, Intestinimonas, Osillibacter and Ruminiclostridium, and further increasing the contents of propionic acid and butyric acid, regulating lipid metabolism and intestinal permeability, and ultimately inhibiting liver inflammation and fat accumulation to alleviate NAFLD. B. adolescentis exerted its effects mainly through changing the intestinal microbiota, increasing the content of propionic acid, regulating lipid metabolism and ultimately inhibiting liver inflammation to alleviate NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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12 pages, 628 KiB

Open AccessArticle

The Change in Metabolic Syndrome Status and the Risk of Nonviral Liver Cirrhosis

by Goh-Eun Chung, Young Chang, Yuri Cho, Eun-Ju Cho, Jeong-Ju Yoo, Sang-Hyun Park, Kyungdo Han, Dong-Wook Shin, Su-Jong Yu, Yoon-Jun Kim and Jung-Hwan Yoon

Biomedicines 2021, 9(12), 1948; https://doi.org/10.3390/biomedicines9121948 - 20 Dec 2021

Cited by 3 | Viewed by 2496

Abstract

Background: Nonalcoholic fatty liver disease is considered to be the hepatic component of metabolic syndrome (MetS). However, the association between changes in MetS status and the risk of liver cirrhosis (LC) has not been investigated to date. This study assessed the association between [...] Read more.

Background: Nonalcoholic fatty liver disease is considered to be the hepatic component of metabolic syndrome (MetS). However, the association between changes in MetS status and the risk of liver cirrhosis (LC) has not been investigated to date. This study assessed the association between changes in MetS and subsequent nonviral LC development. Methods: Data were obtained from the Korean National Health Insurance Service. Individuals who participated in health screenings from both 2009 to 2010 and 2011 to 2012 were included. The primary outcome was LC development according to the static and dynamic MetS status. Subjects were stratified into four groups according to the change in MetS status observed from the two-year interval screening (2009–2011). Cox regression analysis was used to examine the hazard ratios of LC. Results: During a median of 7.3 years of follow-up, 24,923 incident LC cases developed among 5,975,308 individuals. After adjusting for age, sex, smoking, alcohol, regular exercise, and body mass index, the adjusted hazard ratios (95% confidence intervals) for LC development were 1.39 (1.33–1.44) for the MetS-Developed group, 1.32 (1.26–1.37) for the MetS-Recovered group, and 1.51 (1.45–1.56) for the MetS-Sustained group, relative to the MetS-Free group. Stratified analyses according to age, sex, smoking, alcohol intake, exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease showed similar results. Conclusions: Both static and dynamic MetS status are independent risk factors for LC development. The risk of LC was the highest in people with sustained MetS and was lower in the MetS-Recovered group than in the MetS-Sustained group. These results suggest that improving a person’s MetS status may be helpful in preventing LC. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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14 pages, 2894 KiB

Open AccessArticle

Ability of a Combined FIB4/miRNA181a Score to Predict Significant Liver Fibrosis in NAFLD Patients

by Rodrigo Vieira Costa Lima, José Tadeu Stefano, Fernanda de Mello Malta, João Renato Rebello Pinho, Flair José Carrilho, Marco Arrese and Claudia P. Oliveira

Biomedicines 2021, 9(12), 1751; https://doi.org/10.3390/biomedicines9121751 - 24 Nov 2021

Cited by 5 | Viewed by 1751

Abstract

Liver biopsy is the gold standard for assessing fibrosis, but there is a need to seek non-invasive biomarkers for this purpose. The aim of this study was to evaluate the correlation between the serum levels of the microRNAs miR-21, miR-29a, miR-122, miR-155 and [...] Read more.

Liver biopsy is the gold standard for assessing fibrosis, but there is a need to seek non-invasive biomarkers for this purpose. The aim of this study was to evaluate the correlation between the serum levels of the microRNAs miR-21, miR-29a, miR-122, miR-155 and miR-181a and the phenotypic expression of NAFLD. A cross-sectional study was carried out on 108 NAFLD patients diagnosed by liver biopsy. FIB-4 and NAFLD fibrosis scores were calculated. The comparison between the distributions of microRNA values according to the presence or absence of histological fibrosis (F2–F4) was performed. A multivariate logistic regression analysis was performed to build a score for predicting fibrosis using FIB-4 and Ln (miR-181a) as independent variables. Only miR-181a showed a statistical difference between patients with significant liver fibrosis (>F2) and those without (F0–F1) (p = 0.017). FIB-4 revealed an AUC on the ROC curve of 0.667 to predict clinically significant fibrosis (F2–F4). When assessed using the score in association with Ln (miR-181a), there was an improvement in the ROC curve, with an AUC of 0.71. miR-181a can be used as a non-invasive method of predicting fibrosis in NAFLD, and an association with FIB-4 has the potential to increase the accuracy of each method alone. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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19 pages, 12814 KiB

Open AccessArticle

Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

by Keishi Kisoh, Go Sugahara, Yuko Ogawa, Suzue Furukawa, Yuji Ishida, Takeshi Okanoue, Michinori Kohara and Chise Tateno

Biomedicines 2021, 9(11), 1647; https://doi.org/10.3390/biomedicines9111647 - 09 Nov 2021

Cited by 4 | Viewed by 3212

Abstract

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging [...] Read more.

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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16 pages, 3420 KiB

Open AccessArticle

Machine Learning-Based Identification of Potentially Novel Non-Alcoholic Fatty Liver Disease Biomarkers

by Roshan Shafiha, Basak Bahcivanci, Georgios V. Gkoutos and Animesh Acharjee

Biomedicines 2021, 9(11), 1636; https://doi.org/10.3390/biomedicines9111636 - 07 Nov 2021

Cited by 7 | Viewed by 3353

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that presents a great challenge for treatment and prevention.. This study aims to implement a machine learning approach that employs such datasets to identify potential biomarker targets. We developed a pipeline to identify [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that presents a great challenge for treatment and prevention.. This study aims to implement a machine learning approach that employs such datasets to identify potential biomarker targets. We developed a pipeline to identify potential biomarkers for NAFLD that includes five major processes, namely, a pre-processing step, a feature selection and a generation of a random forest model and, finally, a downstream feature analysis and a provision of a potential biological interpretation. The pre-processing step includes data normalising and variable extraction accompanied by appropriate annotations. A feature selection based on a differential gene expression analysis is then conducted to identify significant features and then employ them to generate a random forest model whose performance is assessed based on a receiver operating characteristic curve. Next, the features are subjected to a downstream analysis, such as univariate analysis, a pathway enrichment analysis, a network analysis and a generation of correlation plots, boxplots and heatmaps. Once the results are obtained, the biological interpretation and the literature validation is conducted over the identified features and results. We applied this pipeline to transcriptomics and lipidomic datasets and concluded that the C4BPA gene could play a role in the development of NAFLD. The activation of the complement pathway, due to the downregulation of the C4BPA gene, leads to an increase in triglyceride content, which might further render the lipid metabolism. This approach identified the C4BPA gene, an inhibitor of the complement pathway, as a potential biomarker for the development of NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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18 pages, 1527 KiB

Open AccessArticle

Sex-Dependent Effects of Eicosapentaenoic Acid on Hepatic Steatosis in UCP1 Knockout Mice

by Kembra Albracht-Schulte, Savanna Wilson, Paige Johnson, Mandana Pahlavani, Latha Ramalingam, Bimba Goonapienuwala, Nishan S. Kalupahana, William T. Festuccia, Shane Scoggin, Chanaka N. Kahathuduwa and Naima Moustaid-Moussa

Biomedicines 2021, 9(11), 1549; https://doi.org/10.3390/biomedicines9111549 - 27 Oct 2021

Cited by 1 | Viewed by 1916

Abstract

Visceral obesity may be a driving factor in nonalcoholic fatty liver disease (NAFLD) development. Previous studies have shown that the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), ameliorates obesity in high-fat (HF) fed male, C57Bl/6 mice at thermoneutral conditions, independent of uncoupling protein [...] Read more.

Visceral obesity may be a driving factor in nonalcoholic fatty liver disease (NAFLD) development. Previous studies have shown that the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), ameliorates obesity in high-fat (HF) fed male, C57Bl/6 mice at thermoneutral conditions, independent of uncoupling protein 1 (UCP1). Our goals herein were to investigate sex-dependent mechanisms of EPA in the livers of wild type (WT) and UCP1 knockout (KO) male and female mice fed a HF diet (45% kcal fat; WT-HF, KO-HF) with or without supplementation of 36 g/kg EPA (WT-EPA, KO-EPA). KO significantly increased body weight in males, with no significant reductions with EPA in the WT or KO groups. In females, there were no significant differences in body weight among KO groups and no effects of EPA. In males, liver TGs were significantly higher in the KO-HF group and reduced with EPA, which was not observed in females. Accordingly, gene and protein markers of mitochondrial oxidation, peroxisomal biogenesis and oxidation, as well as metabolic futile cycles were sex-dependently impacted by KO and EPA supplementation. These findings suggest a genotypic difference in response to dietary EPA supplementation on the livers of male and female mice with diet-induced obesity and housed at thermoneutrality. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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10 pages, 248 KiB

Open AccessArticle

The Risk of Colorectal Adenoma in Nonalcoholic or Metabolic-Associated Fatty Liver Disease

by Ji-Yeon Seo, Jung-Ho Bae, Min-Sun Kwak, Jong-In Yang, Su-Jin Chung, Jeong-Yoon Yim, Seon-Hee Lim and Goh-Eun Chung

Biomedicines 2021, 9(10), 1401; https://doi.org/10.3390/biomedicines9101401 - 05 Oct 2021

Cited by 19 | Viewed by 2028

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease associated with various metabolic disorders. Metabolic dysfunction-associated fatty liver disease (MAFLD) emphasizes metabolic dysfunction in NAFLD. Although the relationship between NAFLD and colorectal adenomas has been suggested, the effect of [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease associated with various metabolic disorders. Metabolic dysfunction-associated fatty liver disease (MAFLD) emphasizes metabolic dysfunction in NAFLD. Although the relationship between NAFLD and colorectal adenomas has been suggested, the effect of MAFLD on colorectal adenoma has yet to be investigated. In this study, we examined the relationship between NAFLD/MAFLD and colorectal adenoma in comparison with other metabolic factors. Methods: Examinees who underwent colonoscopy and abdominal ultrasonography on the same day from January 2012 to December 2012 were included. NAFLD was diagnosed according to the findings of ultrasonography. The Fibrosis-4 (FIB-4) index was used as a surrogate marker for advanced hepatic fibrosis. A logistic regression model was used to analyze the risk of NAFLD/MAFLD for colorectal adenoma. Results: The prevalence of NAFLD and MAFLD was 37.5% and 32.8%, respectively. In the multivariate analysis, male sex, older age, diabetes, and smoking increased the risk of colorectal adenoma. NAFLD and MAFLD were the most important risk factors for colorectal adenoma only in females [adjusted odds ratio (OR) 1.43 and 95% confidence interval (CI) 1.01–2.03, and OR 1.55, 95% CI 1.09–2.20, respectively]. NAFLD and MAFLD with an advanced fibrosis index were significantly associated with an increased risk of colorectal adenoma. (NAFLD: OR 1.38, 95% CI, 1.04–1.83, p = 0.027; MAFLD: OR 1.45, 95% CI, 1.13–1.96, p = 0.004, respectively). Conclusion: NAFLD and MAFLD were significantly associated with a higher risk of colorectal adenomas, especially in females. NAFLD and MAFLD with advanced fibrosis were associated with an increased risk of colorectal adenoma. Colonoscopic examinations may be emphasized for patients with NAFLD/MAFLD, for women, or patients with the presence of hepatic fibrosis. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

18 pages, 1969 KiB

Open AccessArticle

Clinical Significance of HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 RNA Panel in NAFLD/NASH Diagnosis: Egyptian Pilot Study

by Reda Albadawy, Sara H. A. Agwa, Eman Khairy, Maha Saad, Naglaa El Touchy, Mohamed Othman and Marwa Matboli

Biomedicines 2021, 9(9), 1248; https://doi.org/10.3390/biomedicines9091248 - 17 Sep 2021

Cited by 11 | Viewed by 2613

Abstract

Background: Non-alcoholic steatohepatitis ((NASH) is the progressive form of (non-alcoholic fatty liver disease) (NAFLD), which can progress to liver cirrhosis and hepatocellular carcinoma. There is no available reliable non-invasive diagnostic tool to diagnose NASH, and still the liver biopsy is the gold standard [...] Read more.

Background: Non-alcoholic steatohepatitis ((NASH) is the progressive form of (non-alcoholic fatty liver disease) (NAFLD), which can progress to liver cirrhosis and hepatocellular carcinoma. There is no available reliable non-invasive diagnostic tool to diagnose NASH, and still the liver biopsy is the gold standard in diagnosis. In this pilot study, we aimed to evaluate the Nod-like receptor (NLR) signaling pathway related RNA panel in the diagnosis of NASH. Methods: Bioinformatics analysis was done, with retrieval of the HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 RNA panel based on the relation to the NLR-signaling pathway. Hepatitis serum markers, lipid profile, NAFLD score and fibrosis score were assessed in the patients’ sera. Reverse transcriptase real time polymerase chain reaction (RT-PCR) was done to assess the relative expression of the RNA panel among patients who had NAFLD without steatosis, NAFLD with simple steatosis, NASH and healthy controls. Results: We observed up-regulation of Lnc-SPARCL1-1:2 lncRNA that led to upregulation of miR-6881-5P with a subsequent increase in levels of HSPD1, MMP14, and ITGB1 mRNAs. In addition, ROC curve analysis was done, with discriminative cutoff values that aided discrimination between NASH cases and control, and also between NAFLD, simple steatosis and NASH. Conclusion: This pilot study concluded that HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 panel expression has potential in the diagnosis of NASH, and also differentiation between NAFLD, simple steatosis and NASH cases. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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18 pages, 2136 KiB

Open AccessArticle

Modelling Nonalcoholic Steatohepatitis In Vivo—A Close Transcriptomic Similarity Supports the Guinea Pig Disease Model

by Josephine Skat-Rørdam, David H. Ipsen, Stefan E. Seemann, Markus Latta, Jens Lykkesfeldt and Pernille Tveden-Nyborg

Biomedicines 2021, 9(9), 1198; https://doi.org/10.3390/biomedicines9091198 - 10 Sep 2021

Cited by 5 | Viewed by 2503

Abstract

The successful development of effective treatments against nonalcoholic steatohepatitis (NASH) is significantly set back by the limited availability of predictive preclinical models, thereby delaying and reducing patient recovery. Uniquely, the guinea pig NASH model develops hepatic histopathology and fibrosis resembling that of human [...] Read more.

The successful development of effective treatments against nonalcoholic steatohepatitis (NASH) is significantly set back by the limited availability of predictive preclinical models, thereby delaying and reducing patient recovery. Uniquely, the guinea pig NASH model develops hepatic histopathology and fibrosis resembling that of human patients, supported by similarities in selected cellular pathways. The high-throughput sequencing of guinea pig livers with fibrotic NASH (n = 6) and matched controls (n = 6) showed a clear separation of the transcriptomic profile between NASH and control animals. A comparison to NASH patients with mild disease (GSE126848) revealed a 45.2% overlap in differentially expressed genes, while pathway analysis showed a 34% match between the top 50 enriched pathways in patients with advanced NASH (GSE49541) and guinea pigs. Gene set enrichment analysis highlighted the similarity to human patients (GSE49541), also when compared to three murine models (GSE52748, GSE38141, GSE67680), and leading edge genes THRSP, CCL20 and CD44 were highly expressed in both guinea pigs and NASH patients. Nine candidate genes were identified as highly correlated with hepatic fibrosis (correlation coefficient > 0.8), and showed a similar expression pattern in NASH patients. Of these, two candidate genes (VWF and SERPINB9) encode secreted factors, warranting further investigations as potential biomarkers of human NASH progression. This study demonstrates key similarities in guinea pig and human NASH, supporting increased predictability when translating research findings to human patients. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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Review

Jump to: Editorial, Research, Other

14 pages, 519 KiB

Open AccessReview

Potential Therapeutic Targets and Promising Agents for Combating NAFLD

by Atsushi Umemura, Seita Kataoka, Keiichiro Okuda, Yuya Seko, Kanji Yamaguchi, Michihisa Moriguchi, Takeshi Okanoue and Yoshito Itoh

Biomedicines 2022, 10(4), 901; https://doi.org/10.3390/biomedicines10040901 - 14 Apr 2022

Cited by 7 | Viewed by 2811

Abstract

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, [...] Read more.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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24 pages, 1405 KiB

Open AccessReview

Gut Microbiome in Non-Alcoholic Fatty Liver Disease: From Mechanisms to Therapeutic Role

by Haripriya Gupta, Byeong-Hyun Min, Raja Ganesan, Yoseph Asmelash Gebru, Satya Priya Sharma, Eunju Park, Sung-Min Won, Jin-Ju Jeong, Su-Been Lee, Min-Gi Cha, Goo-Hyun Kwon, Min-Kyo Jeong, Ji-Ye Hyun, Jung-A. Eom, Hee-Jin Park, Sang-Jun Yoon, Mi-Ran Choi, Dong-Joon Kim and Ki-Tae Suk

Biomedicines 2022, 10(3), 550; https://doi.org/10.3390/biomedicines10030550 - 25 Feb 2022

Cited by 14 | Viewed by 6033

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental pathophysiology of NAFLD is complex and multifactor-driven. In addition to viruses, metabolic syndrome and alcohol, evidence has recently indicated that the microbiome is related to the development and progression of NAFLD. In this review, we summarize the possible microbiota-based therapeutic approaches and highlight the importance of establishing the diagnosis of NAFLD through the different spectra of the disease via the gut–liver axis. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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14 pages, 1171 KiB

Open AccessReview

The Role of Gut–Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC

by Qian Song and Xiang Zhang

Biomedicines 2022, 10(3), 524; https://doi.org/10.3390/biomedicines10030524 - 23 Feb 2022

Cited by 40 | Viewed by 7150

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most prevalent chronic liver diseases worldwide due to the rapidly rising prevalence of obesity and metabolic syndrome. As a hepatic manifestation of metabolic disease, NAFLD begins with hepatic fat accumulation and progresses [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most prevalent chronic liver diseases worldwide due to the rapidly rising prevalence of obesity and metabolic syndrome. As a hepatic manifestation of metabolic disease, NAFLD begins with hepatic fat accumulation and progresses to hepatic inflammation, termed as non-alcoholic steatohepatitis (NASH), hepatic fibrosis/cirrhosis, and finally leading to NAFLD-related hepatocellular carcinoma (NAFLD-HCC). Accumulating evidence showed that the gut microbiome plays a vital role in the initiation and progression of NAFLD through the gut–liver axis. The gut–liver axis is the mutual communication between gut and liver comprising the portal circulation, bile duct, and systematic circulation. The gut microbiome dysbiosis contributes to NAFLD development by dysregulating the gut–liver axis, leading to increased intestinal permeability and unrestrained transfer of microbial metabolites into the liver. In this review, we systematically summarized the up-to-date information of gut microbiome dysbiosis and metabolomic changes along the stages of steatosis, NASH, fibrosis, and NAFLD-HCC. The components and functions of the gut–liver axis and its association with NAFLD were then discussed. In addition, we highlighted current knowledge of gut microbiome-based treatment strategies targeting the gut–liver axis for preventing NAFLD and its associated HCC. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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12 pages, 976 KiB

Open AccessReview

Hypercoagulability in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD): Causes and Consequences

by Armando Tripodi, Rosa Lombardi, Massimo Primignani, Vincenzo La Mura, Flora Peyvandi and Anna L. Fracanzani

Biomedicines 2022, 10(2), 249; https://doi.org/10.3390/biomedicines10020249 - 24 Jan 2022

Cited by 15 | Viewed by 3914

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is anticipated that it could become even more prevalent in parallel with an increase in the incidence of metabolic diseases closely related to NAFLD, such as obesity, type II [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is anticipated that it could become even more prevalent in parallel with an increase in the incidence of metabolic diseases closely related to NAFLD, such as obesity, type II diabetes, dyslipidemia, and arterial hypertension. In addition to liver impairment, NAFLD is associated with cardiovascular diseases. Fibrosis, atherosclerosis, and venous thrombosis are basically the pathogenic mechanisms behind these clinical manifestations, and all are plausibly associated with hypercoagulability that may, in turn, develop because of an imbalance of pro- vs. anticoagulants and the presence of such procoagulant molecular species as microvesicles, neutrophil extracellular traps (NETs), and inflammation. The assessment of hypercoagulability by means of thrombin generation is a global procedure that mimics the coagulation process occurring in vivo much better than any other coagulation test, and is considered to be the best candidate laboratory tool for assessing, with a single procedure, the balance of coagulation in NAFLD. In addition to defining the state of hypercoagulability, the assessment of thrombin generation could also be used to investigate, in clinical trials, the best approach (therapeutic and/or lifestyle changes) for minimizing hypercoagulability and, hence, the risk of cardiovascular diseases, progression to atherosclerosis, and liver fibrosis in patients with NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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16 pages, 1161 KiB

Open AccessReview

Unveiling the Role of the Fatty Acid Binding Protein 4 in the Metabolic-Associated Fatty Liver Disease

by Juan Moreno-Vedia, Josefa Girona, Daiana Ibarretxe, Lluís Masana and Ricardo Rodríguez-Calvo

Biomedicines 2022, 10(1), 197; https://doi.org/10.3390/biomedicines10010197 - 17 Jan 2022

Cited by 11 | Viewed by 4321

Abstract

Metabolic-associated fatty liver disease (MAFLD), the main cause of chronic liver disease worldwide, is a progressive disease ranging from fatty liver to steatohepatitis (metabolic-associated steatohepatitis; MASH). Nevertheless, it remains underdiagnosed due to the lack of effective non-invasive methods for its diagnosis and staging. [...] Read more.

Metabolic-associated fatty liver disease (MAFLD), the main cause of chronic liver disease worldwide, is a progressive disease ranging from fatty liver to steatohepatitis (metabolic-associated steatohepatitis; MASH). Nevertheless, it remains underdiagnosed due to the lack of effective non-invasive methods for its diagnosis and staging. Although MAFLD has been found in lean individuals, it is closely associated with obesity-related conditions. Adipose tissue is the main source of liver triglycerides and adipocytes act as endocrine organs releasing a large number of adipokines and pro-inflammatory mediators involved in MAFLD progression into bloodstream. Among the adipocyte-derived molecules, fatty acid binding protein 4 (FABP4) has been recently associated with fatty liver and additional features of advanced stages of MAFLD. Additionally, emerging data from preclinical studies propose FABP4 as a causal actor involved in the disease progression, rather than a mere biomarker for the disease. Therefore, the FABP4 regulation could be considered as a potential therapeutic strategy to MAFLD. Here, we review the current knowledge of FABP4 in MAFLD, as well as its potential role as a therapeutic target for this disease. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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19 pages, 1525 KiB

Open AccessReview

From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

by Alexandra Gatzios, Matthias Rombaut, Karolien Buyl, Joery De Kock, Robim M. Rodrigues, Vera Rogiers, Tamara Vanhaecke and Joost Boeckmans

Biomedicines 2022, 10(1), 161; https://doi.org/10.3390/biomedicines10010161 - 12 Jan 2022

Cited by 3 | Viewed by 3263

Abstract

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver [...] Read more.

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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14 pages, 598 KiB

Open AccessReview

Prevalence, Risk Factors, and Pathophysiology of Nonalcoholic Fatty Liver Disease (NAFLD) in Women with Polycystic Ovary Syndrome (PCOS)

by Svetlana Spremović Rađenović, Miljan Pupovac, Mladen Andjić, Jovan Bila, Svetlana Srećković, Aleksandra Gudović, Biljana Dragaš and Nebojša Radunović

Biomedicines 2022, 10(1), 131; https://doi.org/10.3390/biomedicines10010131 - 07 Jan 2022

Cited by 23 | Viewed by 4561

Abstract

Background: Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders in women’s reproductive period of life. The presence of nonalcoholic fatty liver disease NAFLD, one of the leading causes of chronic liver disease in the Western world, is increased [...] Read more.

Background: Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders in women’s reproductive period of life. The presence of nonalcoholic fatty liver disease NAFLD, one of the leading causes of chronic liver disease in the Western world, is increased in women with PCOS. This review aims to present current knowledge in epidemiology, pathophysiology, diagnostics, and treatment of NAFLD in PCOS with an emphasis on the molecular basis of development of NAFLD in PCOS women. Methods: Authors investigated the available data on PCOS and NAFLD by a MEDLINE and Pub Med search during the years 1990–2021 using a combination of keywords such as “PCOS”, “NAFLD”, “steatohepatitis”, “insulin resistance”, “hyperandrogenaemia”, “inflammation”, “adipose tissue”, and “obesity”. Peer-reviewed articles regarding NAFLD and PCOS were included in this manuscript. Additional articles were identified from the references of relevant papers. Results: PCOS and NAFLD are multifactorial diseases, The development of NAFLD in PCOS women is linked to insulin resistance, hyperandrogenemia, obesity, adipose tissue dysfunction, and inflammation. There is the possible role of the gut microbiome, mitochondrial dysfunction, and endocannabinoid system in the maintenance of NAFLD in PCOS women. Conclusions: There is a need for further investigation about the mechanism of the development of NAFLD in PCOS women. New data about the molecular basis of development of NAFLD in PCOS integrated with epidemiological and clinical information could influence the evolution of new diagnostic and therapeutic approaches of NAFLD in PCOS. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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62 pages, 3319 KiB

Open AccessReview

Intestinal Barrier and Permeability in Health, Obesity and NAFLD

by Piero Portincasa, Leonilde Bonfrate, Mohamad Khalil, Maria De Angelis, Francesco Maria Calabrese, Mauro D’Amato, David Q.-H. Wang and Agostino Di Ciaula

Biomedicines 2022, 10(1), 83; https://doi.org/10.3390/biomedicines10010083 - 31 Dec 2021

Cited by 78 | Viewed by 11363

Abstract

The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal [...] Read more.

The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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48 pages, 1334 KiB

Open AccessReview

Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

by Alvaro Santos-Laso, María Gutiérrez-Larrañaga, Marta Alonso-Peña, Juan M. Medina, Paula Iruzubieta, María Teresa Arias-Loste, Marcos López-Hoyos and Javier Crespo

Biomedicines 2022, 10(1), 46; https://doi.org/10.3390/biomedicines10010046 - 26 Dec 2021

Cited by 12 | Viewed by 4995

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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0 pages, 1329 KiB

Open AccessReview

Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis

by Vicneswarry Dorairaj, Siti Aishah Sulaiman, Nadiah Abu and Nor Azian Abdul Murad

Biomedicines 2022, 10(1), 15; https://doi.org/10.3390/biomedicines10010015 - 22 Dec 2021

Cited by 23 | Viewed by 7055

Abstract

The global prevalence of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD), as it is now known, has gradually increased. NAFLD is a disease with a spectrum of stages ranging from simple fatty liver (steatosis) to a severe form [...] Read more.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD), as it is now known, has gradually increased. NAFLD is a disease with a spectrum of stages ranging from simple fatty liver (steatosis) to a severe form of steatosis, nonalcoholic steatohepatitis (NASH), which could progress to irreversible liver injury (fibrosis) and organ failure, and in some cases hepatocellular carcinoma (HCC). Although a liver biopsy remains the gold standard for accurate detection of this condition, it is unsuitable for clinical screening due to a higher risk of death. There is thus an increased need to find alternative techniques or tools for accurate diagnosis. Early detection for NASH matters for patients because NASH is the marker for severe disease progression. This review summarizes the current noninvasive tools for NAFLD diagnosis and their performance. We also discussed potential and newer alternative tools for diagnosing NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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23 pages, 3323 KiB

Open AccessReview

Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem

by Sébastien Le Garf, Véronique Nègre, Rodolphe Anty and Philippe Gual

Biomedicines 2021, 9(12), 1915; https://doi.org/10.3390/biomedicines9121915 - 14 Dec 2021

Cited by 20 | Viewed by 3359

Abstract

Metabolic-associated fatty liver disease (MAFLD), previously called nonalcoholic fatty liver diseases (NAFLD), is one of the most important causes of chronic liver disease worldwide and will likely become the leading cause of end-stage liver disease in the decades ahead. MAFLD covers a continuum [...] Read more.

Metabolic-associated fatty liver disease (MAFLD), previously called nonalcoholic fatty liver diseases (NAFLD), is one of the most important causes of chronic liver disease worldwide and will likely become the leading cause of end-stage liver disease in the decades ahead. MAFLD covers a continuum of liver diseases from fatty liver to nonalcoholic steatohepatitis (NASH), liver fibrosis/cirrhosis and hepatocellular cancer. Importantly, the growing incidence of overweight and obesity in childhood, 4% in 1975 to 18% in 2016, with persisting obesity complications into adulthood, is likely to be harmful by increasing the incidence of severe MAFLD at an earlier age. Currently, MAFLD is the leading form of chronic liver disease in children and adolescents, with a global prevalence of 3 to 10%, pointing out that early diagnosis is therefore crucial. In this review, we highlight the current knowledge concerning the epidemiology, risk factors and potential pathogenic mechanisms, as well as diagnostic and therapeutic approaches, of pediatric MAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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16 pages, 799 KiB

Open AccessReview

Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications

by Wenjing Zai, Wei Chen, Hongrui Liu and Dianwen Ju

Biomedicines 2021, 9(12), 1912; https://doi.org/10.3390/biomedicines9121912 - 14 Dec 2021

Cited by 14 | Viewed by 3919

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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26 pages, 1869 KiB

Open AccessReview

Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism

by Tae Hyun Kim, Dong-Gyun Hong and Yoon Mee Yang

Biomedicines 2021, 9(12), 1903; https://doi.org/10.3390/biomedicines9121903 - 14 Dec 2021

Cited by 19 | Viewed by 6467

Abstract

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily [...] Read more.

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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18 pages, 1832 KiB

Open AccessReview

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

by Ming Yang, Lea Khoukaz, Xiaoqiang Qi, Eric T. Kimchi, Kevin F. Staveley-O’Carroll and Guangfu Li

Biomedicines 2021, 9(12), 1893; https://doi.org/10.3390/biomedicines9121893 - 13 Dec 2021

Cited by 8 | Viewed by 3895

Abstract

Nonalcoholic fatty liver disease (NAFLD) with pathogenesis ranging from nonalcoholic fatty liver (NAFL) to the advanced form of nonalcoholic steatohepatitis (NASH) affects about 25% of the global population. NAFLD is a chronic liver disease associated with obesity, type 2 diabetes, and metabolic syndrome, [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) with pathogenesis ranging from nonalcoholic fatty liver (NAFL) to the advanced form of nonalcoholic steatohepatitis (NASH) affects about 25% of the global population. NAFLD is a chronic liver disease associated with obesity, type 2 diabetes, and metabolic syndrome, which is the most increasing factor that causes hepatocellular carcinoma (HCC). Although advanced progress has been made in exploring the pathogenesis of NAFLD and penitential therapeutic targets, no therapeutic agent has been approved by Food and Drug Administration (FDA) in the United States. Gut microbiota-derived components and metabolites play pivotal roles in shaping intrahepatic immunity during the progression of NAFLD or NASH. With the advance of techniques, such as single-cell RNA sequencing (scRNA-seq), each subtype of immune cells in the liver has been studied to explore their roles in the pathogenesis of NAFLD. In addition, new molecules involved in gut microbiota-mediated effects on NAFLD are found. Based on these findings, we first summarized the interaction of diet-gut microbiota-derived metabolites and activation of intrahepatic immunity during NAFLD development and progression. Treatment options by targeting gut microbiota and important molecular signaling pathways are then discussed. Finally, undergoing clinical trials are selected to present the potential application of treatments against NAFLD or NASH. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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20 pages, 404 KiB

Open AccessReview

Metabolic Associated Fatty Liver Disease in Children—From Atomistic to Holistic

by Cristina Oana Mărginean, Lorena Elena Meliț and Maria Oana Săsăran

Biomedicines 2021, 9(12), 1866; https://doi.org/10.3390/biomedicines9121866 - 09 Dec 2021

Cited by 5 | Viewed by 3206

Abstract

Non-alcoholic fatty liver disease has become the most common chronic liver disease in children due to the alarmingly increasing incidence of pediatric obesity. It is well-documented that MAFLD prevalence is directly related to an incremental increase in BMI. The multiple hits theory was [...] Read more.

Non-alcoholic fatty liver disease has become the most common chronic liver disease in children due to the alarmingly increasing incidence of pediatric obesity. It is well-documented that MAFLD prevalence is directly related to an incremental increase in BMI. The multiple hits theory was designed for providing insights regarding the pathogenesis of steatohepatitis and fibrosis in MAFLD. Recent evidence suggested that the microbiome is a crucial contributor in the pathogenesis of MAFLD. Aside from obesity, the most common risk factors for pediatric MAFLD include male gender, low-birth weight, family history of obesity, MAFLD, insulin resistance, type 2 diabetes mellitus, obstructive sleep apnea, and polycystic ovarium syndrome. Usually, pediatric patients with MAFLD have nonspecific symptoms consisting of fatigue, malaise, or diffuse abdominal pain. A wide spectrum of biomarkers was proposed for the diagnosis of MAFLD and NASH, as well as for quantifying the degree of fibrosis, but liver biopsy remains the key diagnostic and staging tool. Nevertheless, elastography-based methods present promising results in this age group as potential non-invasive replacers for liver biopsy. Despite the lack of current guidelines regarding MAFLD treatment in children, lifestyle intervention was proven to be crucial in the management of these patients. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

18 pages, 2756 KiB

Open AccessReview

The Role of Physical Activity in Nonalcoholic and Metabolic Dysfunction Associated Fatty Liver Disease

by Christian von Loeffelholz, Johannes Roth, Sina M. Coldewey and Andreas L. Birkenfeld

Biomedicines 2021, 9(12), 1853; https://doi.org/10.3390/biomedicines9121853 - 07 Dec 2021

Cited by 11 | Viewed by 3928

Abstract

Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key [...] Read more.

Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key element of NAFLD/MAFLD, prediabetes and T2D. Current treatment guidelines recommend regular physical activity. There is evidence, that physical exercise has impact on a variety of molecular pathways, such as AMP-activated protein kinase and insulin signaling as well as glucose transporter 4 translocation, modulating insulin action, cellular substrate flow and in particular ectopic lipid and glycogen storage in a positive manner. Therefore, physical exercise can lead to substantial clinical benefit in persons with diabetes and/or NAFLD/MAFLD. However, experience from long term observational studies shows that the patients’ motivation to exercise regularly appears to be a major limitation. Strategies to integrate everyday physical activity (i.e., nonexercise activity thermogenesis) in lifestyle treatment schedules might be a promising approach. This review aggregates evidence on the impact of regular physical activity on selected molecular mechanisms as well as clinical outcomes of patients suffering from IR and NAFLD/MAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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17 pages, 713 KiB

Open AccessReview

Exploring the Gamut of Receptor Tyrosine Kinases for Their Promise in the Management of Non-Alcoholic Fatty Liver Disease

by Sayali Bhave and Han Kiat Ho

Biomedicines 2021, 9(12), 1776; https://doi.org/10.3390/biomedicines9121776 - 26 Nov 2021

Cited by 4 | Viewed by 2359

Abstract

Recently, non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant health concern affecting approximately a quarter of the world’s population. NAFLD is a spectrum of liver ailments arising from nascent lipid accumulation and leading to inflammation, fibrosis or even carcinogenesis. Despite its [...] Read more.

Recently, non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant health concern affecting approximately a quarter of the world’s population. NAFLD is a spectrum of liver ailments arising from nascent lipid accumulation and leading to inflammation, fibrosis or even carcinogenesis. Despite its prevalence and severity, no targeted pharmacological intervention is approved to date. Thus, it is imperative to identify suitable drug targets critical to the development and progression of NAFLD. In this quest, a ray of hope is nestled within a group of proteins, receptor tyrosine kinases (RTKs), as targets to contain or even reverse NAFLD. RTKs control numerous vital biological processes and their selective expression and activity in specific diseases have rendered them useful as drug targets. In this review, we discuss the recent advancements in characterizing the role of RTKs in NAFLD progression and qualify their suitability as pharmacological targets. Available data suggests inhibition of Epidermal Growth Factor Receptor, AXL, Fibroblast Growth Factor Receptor 4 and Vascular Endothelial Growth Factor Receptor, and activation of cellular mesenchymal-epithelial transition factor and Fibroblast Growth Factor Receptor 1 could pave the way for novel NAFLD therapeutics. Thus, it is important to characterize these RTKs for target validation and proof-of-concept through clinical trials. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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20 pages, 754 KiB

Open AccessEditor’s ChoiceReview

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

by Eun Jin Sun, Miriam Wankell, Pranavan Palamuthusingam, Craig McFarlane and Lionel Hebbard

Biomedicines 2021, 9(11), 1639; https://doi.org/10.3390/biomedicines9111639 - 08 Nov 2021

Cited by 93 | Viewed by 10429

Abstract

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and [...] Read more.

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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17 pages, 1602 KiB

Open AccessReview

The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments

by Phumelele Yvonne Siphepho, Yi-Ting Liu, Ciniso Sylvester Shabangu, Jee-Fu Huang, Chung-Feng Huang, Ming-Lun Yeh, Ming-Lung Yu and Shu-Chi Wang

Biomedicines 2021, 9(10), 1491; https://doi.org/10.3390/biomedicines9101491 - 17 Oct 2021

Cited by 16 | Viewed by 3744

Abstract

Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as [...] Read more.

Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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14 pages, 991 KiB

Open AccessEditor’s ChoiceSystematic Review

Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease

by Anne Linde Mak, Jenny Lee, Anne-Marieke van Dijk, Yasaman Vali, Guruprasad P. Aithal, Jörn M. Schattenberg, Quentin M. Anstee, M. Julia Brosnan, Mohammad Hadi Zafarmand, Dewkoemar Ramsoekh, Stephen A. Harrison, Max Nieuwdorp, Patrick M. Bossuyt and Adriaan G. Holleboom

Biomedicines 2021, 9(12), 1920; https://doi.org/10.3390/biomedicines9121920 - 15 Dec 2021

Cited by 25 | Viewed by 3693

Abstract

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a [...] Read more.

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77–0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73–0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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19 pages, 2840 KiB

Open AccessSystematic Review

The Visceral Adiposity Index in Non-Alcoholic Fatty Liver Disease and Liver Fibrosis—Systematic Review and Meta-Analysis

by Abdulrahman Ismaiel, Ayman Jaaouani, Daniel-Corneliu Leucuta, Stefan-Lucian Popa and Dan L. Dumitrascu

Biomedicines 2021, 9(12), 1890; https://doi.org/10.3390/biomedicines9121890 - 13 Dec 2021

Cited by 19 | Viewed by 8111

Abstract

(1) Background: In order to avoid a liver biopsy in non-alcoholic fatty liver disease (NAFLD), several noninvasive biomarkers have been studied lately. Therefore, we aimed to evaluate the visceral adiposity index (VAI) in NAFLD and liver fibrosis, in addition to its accuracy in [...] Read more.

(1) Background: In order to avoid a liver biopsy in non-alcoholic fatty liver disease (NAFLD), several noninvasive biomarkers have been studied lately. Therefore, we aimed to evaluate the visceral adiposity index (VAI) in NAFLD and liver fibrosis, in addition to its accuracy in predicting NAFLD and NASH. (2) Methods: We searched PubMed, Embase, Scopus, and Cochrane Library, identifying observational studies assessing the VAI in NAFLD and liver fibrosis. QUADAS-2 was used to evaluate the quality of included studies. The principal summary outcomes were mean difference (MD) and area under the curve (AUC). (3) Results: A total of 24 studies were included in our review. VAI levels were significantly increased in NAFLD (biopsy-proven and ultrasound-diagnosed), simple steatosis vs. controls, and severe steatosis vs. simple steatosis. However, no significant MD was found according to sex, liver fibrosis severity, simple vs. moderate and moderate vs. severe steatosis, pediatric NAFLD, and NASH patients. The VAI predicted NAFLD (AUC 0.767) and NASH (AUC 0.732). (4) Conclusions: The VAI has a predictive value in diagnosing NAFLD and NASH, with significantly increased values in adult NAFLD patients, simple steatosis compared to controls, and severe steatosis compared to simple steatosis. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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