salicylates and Non-alcoholic-Fatty-Liver-Disease

Salsalate, an ester formed by 2 salicylic acid molecules, has beneficial effect against metabolic disorders in clinical trials and in animal studies. This study focused on the mechanistic aspects of salsalate activity against non-alcoholic fatty liver disease (NAFLD). Using high-fat diet (HFD) fed mice, we showed that salsalate treatment decreased body-weight gains, reduced white adipose tissue mass and improved glycaemic control. Mice in salsalate-treated group also had reduced obese adipose tissue and hepatic macrophage infiltration and inflammation and adipogenesis gene expression. Histology analysis revealed predominant decreases in hepatosteatosis, including both macrovesicular and microvesicular steatoses. The treatment reversed AMPK activity repression that was accompanied by reduced caspase-6 activity and cleavage. Enzymatic assay and cell culture studies showed that salsalate promoted AMPK activation by directly activating AMPK. This study links salsalate effect against metabolic disorders to its activity on reversion of AMPK repression in NAFLD mice and on suppression of adipogenic gene induction.

Topics: Adipogenesis; AMP-Activated Protein Kinases; Animals; Caspase 6; Caspase Inhibitors; Diet, High-Fat; Disease Models, Animal; Enzyme Activation; HEK293 Cells; Humans; Metabolic Diseases; Non-alcoholic Fatty Liver Disease; Phosphorylation; Salicylates

Topics: Animals; Choline Deficiency; Disease Models, Animal; DNA Helicases; Epigenesis, Genetic; Gene Deletion; Hepatocytes; Histone Acetyltransferases; Methionine; Mice; NADPH Oxidases; Non-alcoholic Fatty Liver Disease; Nuclear Proteins; Promoter Regions, Genetic; Reactive Oxygen Species; Salicylates; Transcription Factors

Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH.. Transgenic APOE*3Leiden.CETP mice were fed a high-fat and high-cholesterol diet with or without salsalate for 12 and 20 weeks. The effects on body weight, plasma biochemical variables, liver histology and hepatic gene expression were assessed.. Salsalate prevented weight gain, improved dyslipidemia and insulin resistance and ameliorated diet-induced NASH, as shown by decreased hepatic microvesicular and macrovesicular steatosis, reduced hepatic inflammation and reduced development of fibrosis. Salsalate affected lipid metabolism by increasing β-oxidation and decreasing lipogenesis, as shown by the activation of PPAR-α, PPAR-γ co-activator 1β, RXR-α and inhibition of genes controlled by the transcription factor MLXIPL/ChREBP. Inflammation was reduced by down-regulation of the NF-κB pathway, and fibrosis development was prevented by down-regulation of TGF-β signalling.. Salsalate exerted a preventive effect on the development of NASH and progression to fibrosis. These data suggest a clinical application of salsalate in preventing NASH.

Topics: Alanine Transaminase; Animals; Apolipoproteins E; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol Ester Transfer Proteins; Cholesterol, Dietary; Diet, High-Fat; Gene Expression Regulation; Insulin; Lipid Metabolism; Lipogenesis; Liver; Male; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Salicylates