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(American Journal of Pathology. 2005;166:1655-1669.)
© 2005 American Society for Investigative Pathology

The Roles of Leptin and Adiponectin

A Novel Paradigm in Adipocytokine Regulation of Liver Fibrosis and Stellate Cell Biology

Xiaokun Ding^*, Neeraj K. Saxena^*, Songbai Lin^*, Amin Xu, Shanthi Srinivasan^* and Frank A. Anania^*

From the Department of Medicine,^* Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; and the Department of Medicine, The University of Hong Kong, Hong Kong, China

Although leptin is a key adipokine promoting liver fibrosis, adiponectin may prevent liver injury. To determine the role of these adipokines in liver fibrosis and to understand their expression in vivo, fa/fa rats and their lean littermates were subjected to bile duct ligation (BDL). Histomorphometry for collagen and -smooth muscle actin (-SMA) revealed that lean rats, but not fa/fa littermates, had significant fibrosis with abundant hepatic stellate cell (HSC) activation. The lean-BDL rats had significantly higher leptin concentrations in the hepatic vein than lean sham-operated, fa/fa BDL, or fa/fa sham-operated rats. Co-localization of leptin and -SMA in activated HSCs was observed by immunohistochemistry. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis confirmed the presence of leptin and -SMA in activated, but not quiescent, HSCs, whereas only quiescent HSCs synthesized adiponectin mRNA and protein. Adiponectin overexpression in activated HSCs reduced proliferation, augmented apoptosis, and reduced expression of -SMA and proliferating cell nuclear antigen. Adiponectin receptors (AdipoR1 and AdipoR2) were detected in both activated and quiescent HSCs, but only activated HSCs produced significant apoptosis after treatment with either globular or full-length adiponectin. Adiponectin may act to reverse HSC activation, maintain HSC quiescence, or significantly, may have important therapeutic implications in liver fibrosis.

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