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

  • Br J Pharmacol. 2015 Nov;172(22):5293-305. doi: 10.1111/bph.13315.
Wen Liang  1  2 ,  Lars Verschuren  3 ,  Petra Mulder  1 ,  José W A van der Hoorn  1 ,  Joanne Verheij  4 ,  Andrea D van Dam  2 ,  Mariette R Boon  2 ,  Hans M G Princen  1 ,  Louis M Havekes  1  2 ,  Robert Kleemann  1 ,  Anita M van den Hoek  1
Affiliations
  • 1. Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
  • 2. Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
  • 3. Department of Microbiology and Systems Biology, TNO, Zeist, The Netherlands.
  • 4. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
PMID: 26292849 DOI: 10.1111/bph.13315
Abstract

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.

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