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Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function
Author(s) -
Elinav Eran,
Ali Mohammad,
Bruck Rafi,
Brazowski Eli,
Phillips Adam,
Shapira Yami,
Katz Meirav,
Solomon Gila,
Halpern Zamir,
Gertler Arieh
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22584
Subject(s) - hepatic stellate cell , leptin , endocrinology , medicine , fibrosis , thioacetamide , steatohepatitis , liver function , in vivo , hepatic fibrosis , biology , fatty liver , obesity , microbiology and biotechnology , disease
Leptin signaling is involved in T‐cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin‐deficient ob / ob mice do not develop liver fibrosis despite the presence of severe long‐standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly‐isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5‐week to 8‐week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon γ (IFN‐γ) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin‐stimulated effects such as increased expression of α‐smooth muscle actin (α‐SMA), and activation of α1 procollagen promoter. Conclusion: Inhibition of leptin‐enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality. (H EPATOLOGY 2009;49:278‐286.)