title: Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.|Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Wen
authors: http://orcid.org/0000-0002-1412-6507
authors: W
authors: Liang
authors: Department of Microbiology and Systems Biology, TNO, Zeist, The Netherlands.
authors: Lars
authors: L
authors: Verschuren
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors: Petra
authors: P
authors: Mulder
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors: José W A
authors: JW
authors: van der Hoorn
authors: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors: Joanne
authors: J
authors: Verheij
authors: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Andrea D
authors: AD
authors: van Dam
authors: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Mariette R
authors: MR
authors: Boon
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors: Hans M G
authors: HM
authors: Princen
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.|Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Louis M
authors: LM
authors: Havekes
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors: Robert
authors: R
authors: Kleemann
authors: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors: Anita M
authors: AM
authors: van den Hoek
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D002791:Cholesterol, Dietary / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012459:Salicylates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002791:Cholesterol, Dietary; D007328:Insulin; D012459:Salicylates; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C014182:salicylsalicylic acid