Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function.
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 gamma (IFN-gamma) 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 alpha-smooth muscle actin (alpha-SMA), and activation of alpha1 procollagen promoter.


CONCLUSIONS
Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality.
Elinav
Eran
E
Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. erane@tasmc.health.gov.il
Ali
Mohammad
M
Bruck
Rafi
R
Brazowski
Eli
E
Phillips
Adam
A
Shapira
Yami
Y
Katz
Meirav
M
Solomon
Gila
G
Halpern
Zamir
Z
Gertler
Arieh
A
D000818:Animals; D005260:Female; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D023421:Models, Animal; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013853:Thioacetamide
D006727:Hormone Antagonists; D020738:Leptin; D010982:Platelet-Derived Growth Factor; D013853:Thioacetamide