Editorial

4 pages, 182 KiB

Open AccessEditorial

NASH and Systemic Complications: From Basic to Clinical Research

by Sabine Baumgartner and Ronit Shiri-Sverdlov

Biomedicines 2021, 9(12), 1913; https://doi.org/10.3390/biomedicines9121913 - 14 Dec 2021

Cited by 2 | Viewed by 1703

Nonalcoholic fatty liver disease (NAFLD) is known as the hepatic manifestation of the metabolic syndrome, and while most patients develop simple steatosis, up to one-third can develop nonalcoholic steatohepatitis (NASH) [...] Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

Research

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17 pages, 2494 KiB

Open AccessArticle

Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH

by Katharina Luise Hupa-Breier, Janine Dywicki, Björn Hartleben, Freya Wellhöner, Benjamin Heidrich, Richard Taubert, Young-Seon Elisabeth Mederacke, Maren Lieber, Konstantinos Iordanidis, Michael P. Manns, Heiner Wedemeyer, Matthias Hardtke-Wolenski and Elmar Jaeckel

Biomedicines 2021, 9(4), 353; https://doi.org/10.3390/biomedicines9040353 - 30 Mar 2021

Cited by 18 | Viewed by 3361

Abstract

Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been [...] Read more.

Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6C^High and CD4⁺Foxp3⁺ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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16 pages, 815 KiB

Open AccessArticle

Non-Alcoholic Steatohepatitis Decreases Microsomal Liver Function in the Absence of Fibrosis

by Wim Verlinden, Eugénie Van Mieghem, Laura Depauw, Thomas Vanwolleghem, Luisa Vonghia, Jonas Weyler, Ann Driessen, Dirk Callens, Laurence Roosens, Eveline Dirinck, An Verrijken, Luc Van Gaal and Sven Francque

Biomedicines 2020, 8(12), 546; https://doi.org/10.3390/biomedicines8120546 - 27 Nov 2020

Cited by 2 | Viewed by 1643

Abstract

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, [...] Read more.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The ¹³C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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29 pages, 6732 KiB

Open AccessArticle

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

by Mei-Ju Hsu, Isabel Karkossa, Ingo Schäfer, Madlen Christ, Hagen Kühne, Kristin Schubert, Ulrike E. Rolle-Kampczyk, Stefan Kalkhof, Sandra Nickel, Peter Seibel, Martin von Bergen and Bruno Christ

Biomedicines 2020, 8(9), 350; https://doi.org/10.3390/biomedicines8090350 - 14 Sep 2020

Cited by 20 | Viewed by 4649

Abstract

Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were [...] Read more.

Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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Review

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13 pages, 1202 KiB

Open AccessReview

Role of Leptin in Non-Alcoholic Fatty Liver Disease

by Carlos Jiménez-Cortegana, Alba García-Galey, Malika Tami, Pilar del Pino, Isabel Carmona, Soledad López, Gonzalo Alba and Víctor Sánchez-Margalet

Biomedicines 2021, 9(7), 762; https://doi.org/10.3390/biomedicines9070762 - 30 Jun 2021

Cited by 43 | Viewed by 4194

Abstract

Non-alcoholic fatty liver disease (NAFLD), which affects about a quarter of the global population, poses a substantial health and economic burden in all countries, yet there is no approved pharmacotherapy to treat this entity, nor well-established strategies for its diagnosis. Its prevalence has [...] Read more.

Non-alcoholic fatty liver disease (NAFLD), which affects about a quarter of the global population, poses a substantial health and economic burden in all countries, yet there is no approved pharmacotherapy to treat this entity, nor well-established strategies for its diagnosis. Its prevalence has been rapidly driven by increased physical inactivity, in addition to excessive calorie intake compared to energy expenditure, affecting both adults and children. The increase in the number of cases, together with the higher morbimortality that this disease entails with respect to the general population, makes NAFLD a serious public health problem. Closely related to the development of this disease, there is a hormone derived from adipocytes, leptin, which is involved in energy homeostasis and lipid metabolism. Numerous studies have verified the relationship between persistent hyperleptinemia and the development of steatosis, fibrinogenesis and liver carcinogenesis. Therefore, further studies of the role of leptin in the NAFLD spectrum could represent an advance in the management of this set of diseases. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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16 pages, 2691 KiB

Open AccessReview

The Synergy between Organ-on-a-Chip and Artificial Intelligence for the Study of NAFLD: From Basic Science to Clinical Research

by Francesco De Chiara, Ainhoa Ferret-Miñana and Javier Ramón-Azcón

Biomedicines 2021, 9(3), 248; https://doi.org/10.3390/biomedicines9030248 - 02 Mar 2021

Cited by 8 | Viewed by 4109

Abstract

Non-alcoholic fatty liver affects about 25% of global adult population. On the long-term, it is associated with extra-hepatic compliances, multiorgan failure, and death. Various invasive and non-invasive methods are employed for its diagnosis such as liver biopsies, CT scan, MRI, and numerous scoring [...] Read more.

Non-alcoholic fatty liver affects about 25% of global adult population. On the long-term, it is associated with extra-hepatic compliances, multiorgan failure, and death. Various invasive and non-invasive methods are employed for its diagnosis such as liver biopsies, CT scan, MRI, and numerous scoring systems. However, the lack of accuracy and reproducibility represents one of the biggest limitations of evaluating the effectiveness of drug candidates in clinical trials. Organ-on-chips (OOC) are emerging as a cost-effective tool to reproduce in vitro the main NAFLD’s pathogenic features for drug screening purposes. Those platforms have reached a high degree of complexity that generate an unprecedented amount of both structured and unstructured data that outpaced our capacity to analyze the results. The addition of artificial intelligence (AI) layer for data analysis and interpretation enables those platforms to reach their full potential. Furthermore, the use of them do not require any ethic and legal regulation. In this review, we discuss the synergy between OOC and AI as one of the most promising ways to unveil potential therapeutic targets as well as the complex mechanism(s) underlying NAFLD. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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17 pages, 1010 KiB

Open AccessReview

Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

by Daryl Ramai, Waqqas Tai, Michelle Rivera, Antonio Facciorusso, Nicola Tartaglia, Mario Pacilli, Antonio Ambrosi, Christian Cotsoglou and Rodolfo Sacco

Biomedicines 2021, 9(2), 184; https://doi.org/10.3390/biomedicines9020184 - 12 Feb 2021

Cited by 21 | Viewed by 5158

Abstract

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing [...] Read more.

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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21 pages, 636 KiB

Open AccessReview

Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis

by Julio Plaza-Díaz, Patricio Solis-Urra, Jerónimo Aragón-Vela, Fernando Rodríguez-Rodríguez, Jorge Olivares-Arancibia and Ana I. Álvarez-Mercado

Biomedicines 2021, 9(2), 145; https://doi.org/10.3390/biomedicines9020145 - 03 Feb 2021

Cited by 20 | Viewed by 5343

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health threat and dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma. Several reports have demonstrated that liver steatosis is associated with the elevation of certain clinical and biochemical markers but with low predictive potential. In addition, current imaging methods are inaccurate and inadequate for quantification of liver steatosis and do not distinguish clearly between the microvesicular and the macrovesicular types. On the other hand, an unhealthy status usually presents an altered gut microbiota, associated with the loss of its functions. Indeed, NAFLD pathophysiology has been linked to lower microbial diversity and a weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defense and inflammation via toll-like receptor signaling. Moreover, this activation of inflammation in hepatocytes induces progression from simple steatosis to NASH. In the present review, we aim to: (a) summarize studies on both human and animals addressed to determine the impact of alterations in gut microbiota in NASH; (b) evaluate the potential role of such alterations as biomarkers for prognosis and diagnosis of this disorder; and (c) discuss the involvement of microbiota in the current treatment for NAFLD/NASH (i.e., bariatric surgery, physical exercise and lifestyle, diet, probiotics and prebiotics, and fecal microbiota transplantation). Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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12 pages, 1374 KiB

Open AccessReview

Magnesium, Little Known But Possibly Relevant: A Link between NASH and Related Comorbidities

by Jorge Simón, Teresa Cardoso Delgado, Luis Alfonso Martinez-Cruz and Maria Luz Martínez-Chantar

Biomedicines 2021, 9(2), 125; https://doi.org/10.3390/biomedicines9020125 - 27 Jan 2021

Cited by 7 | Viewed by 4121

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by an abnormal hepatic lipid accumulation accompanied by a necro-inflammatory process and a fibrotic response. It comprises from 10% to 30% of cases of patients with non-alcoholic liver disease, which is a global health problem affecting around a [...] Read more.

Non-alcoholic steatohepatitis (NASH) is characterized by an abnormal hepatic lipid accumulation accompanied by a necro-inflammatory process and a fibrotic response. It comprises from 10% to 30% of cases of patients with non-alcoholic liver disease, which is a global health problem affecting around a quarter of the worldwide population. Nevertheless, the development of NASH is often surrounded by a pathological context with other comorbidities, such as cardiovascular diseases, obesity, insulin resistance or type 2 diabetes mellitus. Dietary imbalances are increasingly recognized as the root cause of these NASH-related comorbidities. In this context, a growing concern exists about whether magnesium consumption in the general population is sufficient. Hypomagnesemia is a hallmark of the aforementioned NASH comorbidities, and deficiencies in magnesium are also widely related to the triggering of complications that aggravate NASH or derived pathologies. Moreover, the supplementation of this cation has proved to reduce mortality from hepatic complications. In the present review, the role of magnesium in NASH and related comorbidities has been characterized, unraveling the relevance of maintaining the homeostasis of this cation for the correct functioning of the organism. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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13 pages, 1127 KiB

Open AccessReview

Extracellular Vesicles as Drivers of Non-Alcoholic Fatty Liver Disease: Small Particles with Big Impact

by David Højland Ipsen and Pernille Tveden-Nyborg

Biomedicines 2021, 9(1), 93; https://doi.org/10.3390/biomedicines9010093 - 19 Jan 2021

Cited by 12 | Viewed by 3615

Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading chronic liver disease, negatively affecting the lives of millions of patients worldwide. The complex pathogenesis involves crosstalk between multiple cellular networks, but how the intricate communication between these cells drives disease progression remains to [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading chronic liver disease, negatively affecting the lives of millions of patients worldwide. The complex pathogenesis involves crosstalk between multiple cellular networks, but how the intricate communication between these cells drives disease progression remains to be further elucidated. Furthermore, the disease is not limited to the liver and includes the reprogramming of distant cell populations in different organs. Extracellular vesicles (EVs) have gained increased attention as mediators of cellular communication. EVs carry specific cargos that can act as disease-specific signals both locally and systemically. Focusing on NAFLD advancing to steatohepatitis (NASH), this review provides an update on current experimental and clinical findings of the potential role of EVs in hepatic inflammation and fibrosis, the main contributors to progressive NASH. Particular attention is placed on the characteristics of EV cargos and potential specificity to disease stages, with putative value as disease markers and treatment targets for future investigations. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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21 pages, 6211 KiB

Open AccessReview

Usefulness of Different Imaging Modalities in Evaluation of Patients with Non-Alcoholic Fatty Liver Disease

by Karolina Grąt, Michał Grąt and Olgierd Rowiński

Biomedicines 2020, 8(9), 298; https://doi.org/10.3390/biomedicines8090298 - 21 Aug 2020

Cited by 12 | Viewed by 4060

Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are becoming some of the major health problems in well-developed countries, together with the increasing prevalence of obesity, metabolic syndrome, and all of their systemic complications. As the future prognoses are even more disturbing [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are becoming some of the major health problems in well-developed countries, together with the increasing prevalence of obesity, metabolic syndrome, and all of their systemic complications. As the future prognoses are even more disturbing and point toward further increase in population affected with NAFLD/NASH, there is an urgent need for widely available and reliable diagnostic methods. Consensus on a non-invasive, accurate diagnostic modality for the use in ongoing clinical trials is also required, particularly considering a current lack of any registered drug for the treatment of NAFLD/NASH. The aim of this narrative review was to present current information on methods used to assess liver steatosis and fibrosis. There are several imaging modalities for the assessment of hepatic steatosis ranging from simple density analysis by computed tomography or conventional B-mode ultrasound to magnetic resonance spectroscopy (MRS), magnetic resonance imaging proton density fat fraction (MRI-PDFF) or controlled attenuation parameter (CAP). Fibrosis stage can be assessed by magnetic resonance elastography (MRE) or different ultrasound-based techniques: transient elastography (TE), shear-wave elastography (SWE) and acoustic radiation force impulse (ARFI). Although all of these methods have been validated against liver biopsy as the reference standard and provided good accuracy, the MRS and MRI-PDFF currently outperform other methods in terms of diagnosis of steatosis, and MRE in terms of evaluation of fibrosis. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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16 pages, 590 KiB

Open AccessReview

Depression and Cognitive Impairment—Extrahepatic Manifestations of NAFLD and NASH

by Martina Colognesi, Daniela Gabbia and Sara De Martin

Biomedicines 2020, 8(7), 229; https://doi.org/10.3390/biomedicines8070229 - 21 Jul 2020

Cited by 61 | Viewed by 6648

Abstract

Non-alcoholic fatty liver disease (NAFLD) and its complication non-alcoholic steatohepatitis (NASH) are important causes of liver disease worldwide. Recently, a significant association between these hepatic diseases and different central nervous system (CNS) disorders has been observed in an increasing number of patients. NAFLD-related [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) and its complication non-alcoholic steatohepatitis (NASH) are important causes of liver disease worldwide. Recently, a significant association between these hepatic diseases and different central nervous system (CNS) disorders has been observed in an increasing number of patients. NAFLD-related CNS dysfunctions include cognitive impairment, hippocampal-dependent memory impairment, and mood imbalances (in particular, depression and anxiety). This review aims at summarizing the main correlations observed between NAFLD development and these CNS dysfunctions, focusing on the studies investigating the mechanism(s) involved in this association. Growing evidences point at cerebrovascular alteration, neuroinflammation, and brain insulin resistance as NAFLD/NASH-related CNS manifestations. Since the pharmacological options available for the management of these conditions are still limited, further studies are needed to unravel the mechanism(s) of NAFLD/NASH and their central manifestations and identify effective pharmacological targets. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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23 pages, 918 KiB

Open AccessReview

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

by Yvonne Oligschlaeger and Ronit Shiri-Sverdlov

Biomedicines 2020, 8(2), 28; https://doi.org/10.3390/biomedicines8020028 - 08 Feb 2020

Cited by 36 | Viewed by 9149

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and/or hepatocellular carcinoma. Due to its increasing prevalence, NAFLD is currently a major public health concern. Although a wide variety of preclinical models [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and/or hepatocellular carcinoma. Due to its increasing prevalence, NAFLD is currently a major public health concern. Although a wide variety of preclinical models have contributed to better understanding the pathophysiology of NAFLD, it is not always obvious which model is best suitable for addressing a specific research question. This review provides insights into currently existing models, mainly focusing on murine models, which is of great importance to aid in the identification of novel therapeutic options for human NAFLD. Full article

(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)

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