title: Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist.
abstract: Peroxisome proliferator-activated receptor delta (PPARδ), a member of the nuclear receptor family, is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle, and liver. Here we show that the PPARδ agonist KD3010, but not the well-validated GW501516, dramatically ameliorates liver injury induced by carbon tetrachloride (CCl(4)) injections. Deposition of extracellular matrix proteins was lower in the KD3010-treated group than in the vehicle- or GW501516-treated group. Interestingly, profibrogenic connective tissue growth factor was induced significantly by GW501516, but not by KD3010, following CCl(4) treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for 3 wk. Primary hepatocytes treated with KD3010 but not GW501516 were protected from starvation or CCl(4)-induced cell death, in part because of reduced reactive oxygen species production. In conclusion, our data demonstrate that an orally active PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis, suggesting a possible mechanistic and therapeutic approach in treating patients with chronic liver diseases.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Michael
authors.initials: M
authors.lastname: Haimerl
authors.forename: Yong-Han
authors.initials: YH
authors.lastname: Paik
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Claude
authors.initials: C
authors.lastname: Sirlin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yu
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C573927:4-(2,6-dimethyl-4-(4-trifluoromethoxyphenyl)piperazine-1-sulfonyl)indan-2-carboxylic acid; C425931:GW 501516; D047494:PPAR delta; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; D002251:Carbon Tetrachloride