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Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes

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Author: Liang, W. · Verschuren, L. · Mulder, P. · Hoorn, J.W.A. van der · Verheij, J. · Dam, A.D. van · Boon, M.R. · Princen, H.M.G. · Havekes, L.M. · Kleemann, R. · Hoek, A.M. van den
Source:British Journal of Pharmacology, 22, 172, 5293-5305
Identifier: 528972
doi: doi:10.1111/bph.13315
Keywords: Biology · Alanine aminotransferase · Aspartate aminotransferase · Glucose · High density lipoprotein cholesterol · Insulin · Interleukin 6 · Low density lipoprotein cholesterol · Peroxisome proliferator activated receptor alpha · Salsalate · Triacylglycerol · Alanine aminotransferase blood level · Animal cell · Animal experiment · Animal model · Animal tissue · Aspartate aminotransferase blood level · Body weight · Controlled study · Down regulation · Drug efficacy · Drug response · Dyslipidemia · Energy metabolism · Fatty acid oxidation · Fatty liver · Gene expression · Glucose blood level · Glycemic control · Hepatitis · Insulin blood level · Insulin resistance · Lipid metabolism · Lipogenesis · Male · Mouse · Nonalcoholic fatty liver · Nonhuman · Treatment duration · Treatment outcome · Triacylglycerol blood level · Upregulation · Weight gain · Biomedical Innovation · Healthy Living · Life · MSB - Microbiology and Systems Biology MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences


BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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. Chemicals/CAS: alanine aminotransferase, 9000-86-6, 9014-30-6; aspartate aminotransferase, 9000-97-9; glucose, 50-99-7, 84778-64-3; insulin, 9004-10-8; peroxisome proliferator activated receptor alpha, 147258-70-6; salsalate, 552-94-3