Leptin Promotes the Myofibroblastic Phenotype in Hepatic Stellate Cells by Activating the Hedgehog Pathway

• DOI: 10.1074/jbc.m110.168542
• Publication Date: 2010-09-16T00:27:01Z
• Authors: Steve S. Choi; Wing-Kin Syn; Gamze F. Karaca; Alessia Omenetti; Cynthia A. Moylan; Rafal P. Witek; Kolade M. Agboola; Youngmi Jung; Gregory A. Michel...; Anna Mae Diehl
• Keywords: Hepatic stellate cell; Leptin receptor

Trans-differentiation of quiescent hepatic stellate cells (Q-HSCs), which exhibit epithelial and adipocytic features, into myofibroblastic-HSC (MF-HSCs) is a key event in liver fibrosis. Culture models demonstrated that Hedgehog (Hh) pathway activation required for transition epithelioid/adipocytic Q-HSCs MF-HSCs. Hh signaling inhibits adiposity promotes epithelial-to-mesenchymal transitions (EMTs). Leptin (anti-adipogenic, pro-EMT factor) HSC trans-differentiation fibrosis, suggesting the pathways may interact to modulate cell fate. This study aimed determine whether leptin activates this fibrogenic effects leptin. Cultures primary HSCs from lean fa/fa rats with an inherited ObRb defect were examined. Inhibitors PI3K/Akt, JAK/STAT, used delineate how influenced trans-differentiation. Fibrogenesis was compared wild type db/db mice (impaired function) assess profibrotic role The results demonstrate leptin-ObR interactions activate latter necessary promote Leptin-related increases ObR induction sufficient repress program. Leptin-mediated JAK/STAT mesenchymal gene expression. Leptin-ObRb not occur vitro or vivo but are important because fibrogenesis attenuated mice. These findings reveal alter expression programs control fate have implications fibrosis other leptin-regulated processes involving EMTs, including development, obesity, cancer metastasis.