Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet.
We evaluated the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, and GW501516, a PPARdelta agonist, on mice fed a methionine- and choline-deficient (MCD) diet, a model of non-alcholic steatohepatitis (NASH), to investigate (a) the efficacy of bezafibrate against non-alcholic steatohepatitis and (b) the relation between non-alcholic steatohepatitis and the functional role of PPARdelta. Bezafibrate (50 or 100 mg/kg/day) and GW501516 (10 mg/kg/day) were administered by gavage once a day for 5 weeks. Hepatic lipid contents, plasma triglyceride, high density lipoprotein (HDL)-cholesterol and alanine aminotransferase (ALT) concentrations were evaluated, as were histopathological changes in the liver and hepatic mRNA expression levels. Bezafibrate and GW501516 inhibited the MCD-diet-induced elevations of hepatic triglyceride and thiobarbituric acid-reactants contents and the histopathological increases in fatty droplets within hepatocytes, liver inflammation and number of activated hepatic stellate cells. In this model, bezafibrate and GW501516 increased the levels of hepatic mRNAs associated with fatty acid beta-oxidation [acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-1 (CPT-1), liver-fatty acid binding protein (L-FABP) and peroxisomal ketothiolase], and reduced the levels of those associated with inflammatory cytokines or chemokine [transforming growth factor (TGF)-beta1, interleukin (IL)-6, IL-1beta, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF) alpha and nuclear factor (NF)-kappaB1]. In addition, bezafibrate characteristically reduced the elevation in the level of plasma ALT, but enhanced that in plasma adiponectin and increased the mRNA expression levels of its receptors (adiponectin receptors 1 and 2). These results suggest that (a) bezafibrate (especially) and GW501516 might improve hepatic steatosis via an improvement in fatty acid beta-oxidation and a direct prevention of inflammation, (b) treatment with a PPARdelta agonist might improve non-alcholic steatohepatitis, (c) bezafibrate may improve non-alcholic steatohepatitis via activation not only of PPARalpha but also of PPARdelta, because bezafibrate is a PPAR pan-agonist.
Toxicology Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., 2320-1 Maki, Hotaka, Azumino-city, Nagano-Pref., 399-8305, Japan. tatsuya_nagasawa@pharm.kissei.co.jp
Tatsuya
T
Nagasawa
Yoichi
Y
Inada
Shigeru
S
Nakano
Toru
T
Tamura
Tetsuaki
T
Takahashi
Kazuyasu
K
Maruyama
Yoshinobu
Y
Yamazaki
Junji
J
Kuroda
Nobuo
N
Shibata
D042962:Acyl-CoA Oxidase / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001629:Bezafibrate / Q000008:administration & dosage / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D002794:Choline / Q000008:administration & dosage; D004032:Diet / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005234:Fatty Liver / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000819:agonists; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D008076:Cholesterol, HDL; D050556:Fatty Acid-Binding Proteins; C425931:GW 501516; D015850:Interleukin-6; D047494:PPAR delta; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D013844:Thiazoles; D017392:Thiobarbituric Acid Reactive Substances; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D008715:Methionine; D042962:Acyl-CoA Oxidase; D002334:Carnitine O-Palmitoyltransferase; D000410:Alanine Transaminase; D002794:Choline; D001629:Bezafibrate