The critical role of redox regulation of PTEN and peroxiredoxin III in alcoholic fatty liver

AbstractObesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), however the exact mechanisms remain incompletely understood. Here we demonstrate that macrophage scavenger receptor 1 (MSR1) is associated with the occurrence of hepatic lipid-laden foamy macrophages and correlates with the degree of steatosis and steatohepatitis in a large cohort of NAFLD patients. Mice lacking Msr1 are protected against high fat diet-induced metabolic disorder, showing less hepatic inflammation and fibrosis, reduced circulating fatty acids, increased lipid storage in the adipocytes and improved glucose tolerance. Moreover, MSR1 triggers diet-induced JNK-mediated inflammatory activation of macrophages independent of lipopolysaccharide. Taken together, our data suggest a critical role for MSR1 in lipid homeostasis and a potential therapeutic target for the treatment of NAFLD.One Sentence SummaryThe immunometabolic role of MSR1 in human NAFLD.

Download Full-text

Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies

Biomedicines ◽

10.3390/biomedicines9111660 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1660

Author(s):

Han Zhang ◽

Enxiang Zhang ◽

Hongbo Hu

Keyword(s):

Lipid Peroxidation ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Critical Role ◽

Iron Storage ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Selection Of

Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.

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

The role of cytochrome P-4502E1 in the progression of alcoholic and non-alcoholic fatty liver

Zeitschrift für Gastroenterologie ◽

10.1055/s-0030-1263844 ◽

2010 ◽

Vol 48 (08) ◽

Author(s):

H Qin ◽

K Glassen ◽

G Millonig ◽

KB Linhart ◽

H Bartsch ◽

...

Keyword(s):

Fatty Liver ◽

Alcoholic Fatty Liver

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

Role of Insulin Resistance in MAFLD

International Journal of Molecular Sciences ◽

10.3390/ijms22084156 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4156

Author(s):

Yoshitaka Sakurai ◽

Naoto Kubota ◽

Toshimasa Yamauchi ◽

Takashi Kadowaki

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

De Novo Lipogenesis ◽

Hepatic Insulin Resistance ◽

Metabolic Dysfunction ◽

Alcoholic Fatty Liver ◽

Fat Accumulation

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

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

Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development

Nutrients ◽

10.3390/nu13051442 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1442

Author(s):

Pau Vancells Lujan ◽

Esther Viñas Esmel ◽

Emilio Sacanella Meseguer

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Critical Role ◽

Dietary Treatment ◽

Dietary Interventions ◽

Lifestyle Modifications ◽

Alcoholic Fatty Liver ◽

Effective Form ◽

Unhealthy Diet

NAFLD is the world’s most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharmacotherapeutic treatment for NAFLD. Treatment is therefore based on lifestyle modifications including changes to diet and exercise, although it is unclear what the most effective form of intervention is. The aim of this review, then, is to discuss the role of specific nutrients and the effects of different dietary interventions on NAFLD. It is well established that an unhealthy diet rich in calories, sugars, and saturated fats and low in polyunsaturated fatty acids, fibre, and micronutrients plays a critical role in the development and progression of this disease. However, few clinical trials have evaluated the effects of nutrition interventions on NAFLD. We, therefore, summarise what is currently known about the effects of macronutrients, foods, and dietary patterns on NAFLD prevention and treatment. Most current guidelines recommend low-calorie, plant-based diets, such as the Mediterranean diet, as the most effective dietary pattern to treat NAFLD. More clinical trials are required, however, to identify the best evidence-based dietary treatment approach.

Download Full-text