Leptin is essential for the hepatic fibrogenic response to chronic liver injury.
OBJECTIVE
Obesity is associated with hyperleptinemia and is also a risk factor for fibrosis and severity of fibrosis in several chronic liver diseases. The correlation between increased leptin, obesity and hepatic fibrosis prompted us to hypothesise that leptin has profibrogenic effects on the liver.


METHODS
We analysed the role of leptin in liver fibrosis in leptin-deficient mice fed a diet which generates steatohepatitis, and in chronic carbon tetrachloride-induced hepatic injury.


RESULTS
Leptin-deficient mice failed to develop fibrosis during steatohepatitis or in response to chronic toxic liver injury, and failed to up-regulate collagen-I while developing similar hepatic injury as their genetic controls. Restitution of physiological levels of circulating leptin by injection of exogenous leptin, but not correction of the obese phenotype by dietary manipulation, restored liver fibrosis in leptin-deficient mice during chronic liver injury. These results confirmed the absolute requirement of leptin for hepatic fibrosis. We showed that leptin deficiency did not alter hepatic TNF regulation but that leptin is necessary for induction of bioactive transforming growth factor beta 1 (TGFbeta1) protein in the context of chronic liver injury.


CONCLUSIONS
These data establish that leptin is an essential mediator of hepatic fibrosis in response to chronic liver injury, whether metabolic or toxic in aetiology.
Storr Liver Unit, Department of Medicine and Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW 2145, Australia. isabelle_leclercq@wmi.usyd.edu.au
Isabelle A
IA
Leclercq
Geoffrey C
GC
Farrell
Rixt
R
Schriemer
Graham R
GR
Robertson
D000818:Animals; D002251:Carbon Tetrachloride; D002908:Chronic Disease; D018450:Disease Progression; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D020738:Leptin / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020738:Leptin; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride