metallothionein and Non-alcoholic-Fatty-Liver-Disease

Non-alcoholic fatty liver disease (NAFLD), a metabolic disorder that develops from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), has become an epidemic of chronic liver dysfunction worldwide. However, mechanisms that govern the transition from NAFL to NASH have not been fully elucidated.. Gene expression profile data of NAFLD liver tissues were obtained from Gene Expression Omnibus (GEO), including three microarray datasets with 60 NAFL and 44 NASH patients. Integrative differentially expressed genes (DEGs) between NAFL and NASH patients were identified using robust rank aggregation (RRA) analysis. Hub genes were identified combined with gene ontology functional annotation and protein-protein interaction network construction and validated using a sequencing dataset. Huh-7 cells with palmitate-induced lipid overload and NAFLD-diet mouse model of different stages were used to verify our findings.. RRA analysis determined 70 robust DEGs between NAFL and NASH. The most robustly upregulated genes were. Our integrated analysis identified novel gene signatures and provided comprehensive molecular mechanisms underlying the transition from NAFL to NASH. Metallothionein might be a potential intervention target for NAFLD progression.

Topics: Animals; Diet; Disease Models, Animal; Metallothionein; Mice; Non-alcoholic Fatty Liver Disease; Protein Interaction Maps

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose+atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid β-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x 0.45) and its target genes, and increased the hepatic activity of the fatty acid β-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion.

Topics: Animals; Atorvastatin; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cyclic AMP-Dependent Protein Kinases; Dietary Carbohydrates; Disease Models, Animal; Down-Regulation; Fatty Acids; Fatty Liver; Fructokinases; Fructose; Gene Expression Regulation; Hepatitis; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; I-kappa B Proteins; Inflammation Mediators; Lipid Metabolism; Liver; Male; Metallothionein; Necrosis; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Phosphorylation; Pyrroles; Rats; Rats, Sprague-Dawley; Triglycerides