title: Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals.
abstract: Lines of evidence suggested a possible link between leptin and hepatic fibrosis; however, whether leptin modulates the fibrogenesis in the liver remains unclear. The purpose of this study, therefore, was to evaluate the effect of leptin on inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. Male C57Bl/6 mice were given carbon tetrachloride (CCl(4)) (0.1 microL/g body weight [BW], intraperitoneally [IP]) and/or recombinant murine leptin (1 microg/g BW, IP) simultaneously, and sacrificed up to 72 hours later. Further, some mice were given thioacetamide (TAA; 200 microg/g BW, IP) and leptin 3 times per week for 4 weeks to evaluate the effect of leptin on chronic fibrogenic responses. A simultaneous injection of leptin enhanced acute CCl(4)-induced necroinflammatory and subsequent fibrotic changes in the hepatic lobules. The steady-state messenger RNA (mRNA) levels of alpha1(I) procollagen and heat shock protein 47 (HSP47) in the liver were potentiated when leptin was injected together with CCl(4). Expression of alpha smooth muscle actin (alpha-SMA) in the liver after CCl(4) treatment was also augmented markedly in combination with leptin. Further, leptin increased transforming growth factor beta1 (TGF-beta1) mRNA in the liver 24 hours after acute CCl(4) about 4-fold higher than CCl(4) alone. Moreover, leptin enhanced hepatic fibrosis and induction of alpha1(I) procollagen mRNA caused by chronic TAA administration. Collectively, these findings indicated that leptin augments both inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. It is postulated that the increase in systemic leptin levels enhances up-regulation of TGF-beta1, leading to activation of stellate cells, thereby augmenting the fibrogenic response in the liver.
authors.affiliation: Department of Gastroenterology and Division of Biochemistry, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ikejima
authors.forename: H
authors.initials: H
authors.lastname: Honda
authors.forename: M
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: M
authors.initials: M
authors.lastname: Hirose
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.forename: N
authors.initials: N
authors.lastname: Sato
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004731:Endotoxins / Q000097:blood; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics; D020738:Leptin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D011168:Portal System; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013853:Thioacetamide; D000637:Transaminases / Q000097:blood; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D004731:Endotoxins; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D020738:Leptin; D011347:Procollagen; D012333:RNA, Messenger; C494661:Serpinh1 protein, mouse; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D000637:Transaminases