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Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function†
Article first published online: 19 AUG 2008
Copyright © 2008 American Association for the Study of Liver Diseases
Volume 49, Issue 1, pages 278–286, January 2009
How to Cite
Elinav, E., Ali, M., Bruck, R., Brazowski, E., Phillips, A., Shapira, Y., Katz, M., Solomon, G., Halpern, Z. and Gertler, A. (2009), Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function. Hepatology, 49: 278–286. doi: 10.1002/hep.22584
Potential conflict of interest: Dr. Gertler owns stock in, is an employee of, and received travel grants from Protein Laboratories Rehovot (PLR) Ltd.
- Issue published online: 28 DEC 2008
- Article first published online: 19 AUG 2008
- Accepted manuscript online: 19 AUG 2008 12:00AM EST
- Manuscript Accepted: 12 AUG 2008
- Manuscript Received: 8 JUN 2008
- Israeli Science Foundation. Grant Number: 521/07
- Weizmann Institute of Science–Tel Aviv Medical Center Research Fund
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. (HEPATOLOGY 2009;49:278-286.)