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Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals
Author(s) -
Ikejima Kenichi,
Honda Hajime,
Yoshikawa Mutsuko,
Hirose Miyoko,
Kitamura Tsuneo,
Takei Yoshiyuki,
Sato Nobuhiro
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.26518
Subject(s) - leptin , thioacetamide , endocrinology , medicine , procollagen peptidase , fibrosis , hepatic stellate cell , chemistry , hepatic fibrosis , carbon tetrachloride , obesity , organic chemistry
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 μL/g body wieght [BW], intraperitoneally [IP]) and/or recombinant murine leptin (1 μg/g BW, IP) simultaneously, and sacrificed up to 72 hours later. Further, some mice were given thioacetamide (TAA; 200 μg/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 α1(I) procollagen and heat shock protein 47 (HSP47) in the liver were potentiated when leptin was injected together with CCl 4 . Expression of α smooth muscle actin (α‐SMA) in the liver after CCl 4 treatment was also augmented markedly in combination with leptin. Further, leptin increased transforming growth factor β1 (TGF‐β1) 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 α1(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‐β1, leading to activation of stellate cells, thereby augmenting the fibrogenic response in the liver.