title: Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4 -induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase.
  
  
  CONCLUSIONS
  The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms.
authors.affiliation: Institut Pasteur de Lille, Lille, France; Inserm, UMR1011, Lille, France; Université Lille Nord de France, Lille, France; Université Droit et Santé de Lille, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Anne
authors.initials: A
authors.lastname: Rubenstrunk
authors.forename: Benoit
authors.initials: B
authors.lastname: Noel
authors.forename: Géraldine
authors.initials: G
authors.lastname: Rigou
authors.forename: Philippe
authors.initials: P
authors.lastname: Delataille
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Millatt
authors.forename: Morgane
authors.initials: M
authors.lastname: Baron
authors.forename: Anthony
authors.initials: A
authors.lastname: Lucas
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.forename: Dean W
authors.initials: DW
authors.lastname: Hum
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.forename: Rémy
authors.initials: R
authors.lastname: Hanf
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy; D047188:Chalcones / Q000627:therapeutic use*; D050171:Dyslipidemias / Q000188:drug therapy; D005234:Fatty Liver / Q000188:drug therapy* / Q000517:prevention & control; D006801:Humans; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000517:prevention & control; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000819:agonists* / Q000627:therapeutic use; D047494:PPAR delta / Q000819:agonists* / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use*; D051381:Rats
chemical_list: C585906:2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid; D047188:Chalcones; D047493:PPAR alpha; D047494:PPAR delta; D011422:Propionates; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase