The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

Download Full-text

Hypoxia-Inducible Factors as Key Players in the Pathogenesis of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis

Frontiers in Medicine ◽

10.3389/fmed.2021.753268 ◽

2021 ◽

Vol 8 ◽

Author(s):

Lorenz M. W. Holzner ◽

Andrew J. Murray

Keyword(s):

Transcription Factors ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Treatment Options ◽

Redox Homeostasis ◽

Health Concern ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) are a major public health concern with high and increasing global prevalence, and a significant disease burden owing to its progression to more severe forms of liver disease and the associated risk of cardiovascular disease. Treatment options, however, remain scarce, and a better understanding of the pathological and physiological processes involved could enable the development of new therapeutic strategies. One process implicated in the pathology of NAFLD and NASH is cellular oxygen sensing, coordinated largely by the hypoxia-inducible factor (HIF) family of transcription factors. Activation of HIFs has been demonstrated in patients and mouse models of NAFLD and NASH and studies of activation and inhibition of HIFs using pharmacological and genetic tools point toward important roles for these transcription factors in modulating central aspects of the disease. HIFs appear to act in several cell types in the liver to worsen steatosis, inflammation, and fibrosis, but may nevertheless improve insulin sensitivity. Moreover, in liver and other tissues, HIF activation alters mitochondrial respiratory function and metabolism, having an impact on energetic and redox homeostasis. This article aims to provide an overview of current understanding of the roles of HIFs in NAFLD, highlighting areas where further research is needed.

Download Full-text

Role of MicroRNAs in Pathophysiology of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis

Middle East Journal of Digestive Diseases ◽

10.15171/mejdd.2018.113 ◽

2018 ◽

Vol 10 (4) ◽

pp. 213-219 ◽

Cited By ~ 4

Author(s):

Farzaneh Iravani ◽

Neda Hosseini ◽

Majid Mojarrad

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Critical Role ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Specificity And Sensitivity ◽

Wide Range ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. It includes wide range of diseases from different subtypes of simple steatosis to non-alcoholic steatohepatitis (NASH), which may be complicated by liver fibrosis, cirrhosis, or hepatocellular carcinoma. Of the epigenetic factors that play a key role in the progression of it, is microRNAs (miRNAs). MiRNAs are short non-coding RNAs of 22-23 nucleotides in length, which regulate a large number of genes that have a critical role in regulation of lipid and cholesterol biosynthesis in hepatocytes. MiRNAs can be used as a very powerful biomarker to diagnosis and follow-up any disorder, such as NAFLD and NASH with a high specificity and sensitivity. The aim of this study was to review the role of different miRNAs in the pathophysiology of NASH and NAFLD.

Download Full-text

Prevalence, diagnosis and treatment with 3 different statins of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in military personnel. Do genetics play a role?

Current Vascular Pharmacology ◽

10.2174/1570161118666201015152921 ◽

2020 ◽

Vol 18 ◽

Author(s):

Georgios Sfikas ◽

Michael Psallas ◽

Charalambos Koumaras ◽

Konstantinos Imprialos ◽

Evangelos Perdikakis ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Military Personnel ◽

Fatty Liver Disease ◽

Exercise Group ◽

Severe Form ◽

Laboratory Evaluation ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), are major health problems worldwide. Genetics may play a role in the pathogenesis of NAFLD/NASH. Aim: To investigate the prevalence of NAFLD/NASH in 5,400 military personnel and evaluate the effect of treatment with 3 statins on NAFLD/NASH using 2 non-invasive scores [NAFLD Activity Score (NAS); Fibrosis-4 score (FIB-4)]. Methods: During the mandatory annual medical check-up, military personnel underwent a clinical and laboratory evaluation. Participants with NAFLD/NASH were randomised to 4 groups (n=151 each): dietexercise, atorvastatin, rosuvastatin or pitavastatin for 1 year (i.e. until the next routine evaluation). Results: From all the participants, 613 had NAFLD/NASH (prevalence 11.3 vs 39.8% in the general population, p<0.001); 604 consented to participate in the study. After a year of treatment, the diet-exercise group showed no significant changes in both scores (NAS 4.98 baseline vs 5.62, p=0.07; FIB-4 3.42 vs 3.52, p=0.7). For the atorvastatin group, both scores were reduced (NAS 4.97 vs 1.95, p<0.001, FIB-4 3.56 vs 0.83, p<0.001), for rosuvastatin (NAS 5.55 vs 1.81, p<0.001, FIB-4 3.61 vs 0.79, p<0.001), and for pitavastatin (NAS 4.89 vs 1.99, p<0.001, FIB-4 3.78 vs 0.87, p<0.001). Conclusions : Atorvastatin, rosuvastatin and pitavastatin have a beneficial and safe effect in NAFLD/NASH patients as recorded by the improvement in the NAS (representing NAFLD activity) and FIB-4 (representing liver fibrosis) scores. Since both those with and without NAFLD/NASH shared several baseline characteristics, genetics may play a role in the pathogenesis of NAFLD/NASH and its treatment with statins.

Download Full-text

Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis

10.1002/14651858.cd005166 ◽

2005 ◽

Cited By ~ 1

Author(s):

F Angelico ◽

C Alessandri ◽

M Burattin ◽

M Del Ben ◽

S Orando ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Alcoholic Fatty Liver Disease

Download Full-text

The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

Journal of Clinical Medicine ◽

10.3390/jcm10051081 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1081

Author(s):

Mikkel Parsberg Werge ◽

Adrian McCann ◽

Elisabeth Douglas Galsgaard ◽

Dorte Holst ◽

Anne Bugge ◽

...

Keyword(s):

Liver Disease ◽

Animal Models ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Precise Control ◽

Transsulfuration Pathway ◽

Global Population ◽

Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

Download Full-text

Expert Opinion on the Management of Non-Alcoholic Fatty Liver Disease (NAFLD) in the Middle East with a Focus on the Use of Silymarin

Gastroenterology Insights ◽

10.3390/gastroent12020014 ◽

2021 ◽

Vol 12 (2) ◽

pp. 155-165

Author(s):

Ahmed Hashem ◽

Yogesh Shastri ◽

Malfi Al Otaibi ◽

Elwin Buchel ◽

Hussam Saleh ◽

...

Keyword(s):

Liver Disease ◽

Middle East ◽

Fatty Liver Disease ◽

Expert Panel ◽

Treatment Options ◽

Current Treatment ◽

Alcoholic Fatty Liver ◽

Liver Disease Progression ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty disease (NAFLD) is amongst the leading causes of chronic liver disease worldwide. The prevalence of NAFLD in the Middle East is 32%, similar to that observed worldwide. The clinicians in this region face several challenges in diagnosing and treating patients with NAFLD. Additionally, there are no national or regional guidelines to address the concerns faced with current treatment options. Silymarin, derived from milk thistle, provides a rational and clinically proven approach to hepatoprotection. This article focuses on addressing regional diagnostic challenges and provides clear guidance and potential solutions for the use of Silymarin in the treatment of NAFLD in the Middle East. Both clinical and preclinical studies have highlighted the efficiency of Silymarin in managing NAFLD by reducing liver disease progression and improving patient symptoms and quality of life, alongside being safe and well tolerated. An expert panel of professionals from the Middle East convened to establish a set of regional-specific diagnostics. A consensus was established to aid general physicians to address the diagnostic challenges in the region. In conclusion, Silymarin can be considered beneficial in treating NAFLD and should be initiated as early as possible and continued as long as necessary.

Download Full-text

The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Biomedicines ◽

10.3390/biomedicines9060687 ◽

2021 ◽

Vol 9 (6) ◽

pp. 687

Author(s):

Daniela Gabbia ◽

Luana Cannella ◽

Sara De De Martin

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Current Knowledge ◽

Mechanisms Of Action ◽

Nadph Oxidases ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

Download Full-text

Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

Biomedicines ◽

10.3390/biomedicines9020184 ◽

2021 ◽

Vol 9 (2) ◽

pp. 184

Author(s):

Daryl Ramai ◽

Waqqas Tai ◽

Michelle Rivera ◽

Antonio Facciorusso ◽

Nicola Tartaglia ◽

...

Keyword(s):

Public Health ◽

Hepatocellular Carcinoma ◽

Lipid Peroxidation ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Natural Progression ◽

Public Health Threat ◽

Alcoholic Fatty Liver Disease

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.

Download Full-text