Kupffer cells mediate leptin-induced liver fibrosis (Gastroenterology, 2009, 137:713-723)

報告日期: 2010/06/01
報告時間: 15:10/16:00
報告學生: 劉鈺亭
講評老師: 蔡曜聲


Kupffer Cells Mediate Leptin-Induced Liver Fibrosis


Wang J et al. Gastroenterology, 2009, 137:713-723.



Commentator:蔡曜聲 老師

Date2010/06/01 15:10-16:00

PlaceRoom 602



Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms of this process are unclear. The purpose of this paper is to demonstrate the direct and indirect effects of leptin on liver fibrosis. The authors found that hepatic stellate cells (HSCs) were not activated by incubation with leptin. However, HSCs cultured with conditioned medium from leptin-treated kupffer cells (KCs) significantly increased gene expression of fibrosis mediators, such as collagen I (collagen-1), tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor β1 (TGF-β1), and connective tissue growth factor (CTGF/CCN2). Leptin-treated KC-conditioned medium elevated α-smooth muscle actin (αSMA) protein levels. α-SMA is a marker of HSC activation. The authors also showed that KCs isolated from leptin receptor-deficient Zucker (fa/fa) rats did not activate HSCs. Under leptin treatment, messenger RNA and protein expression of TGF-β1 and CTGF/CCN2 were increased in KCs. Furthermore, Leptin activates the phosphorylation of the signal transducer, activator of transcription-3 (STAT 3), AKT, and extracellular signal-related kinase 1/2 (ERK1/2), as well as activates the transcription factors AP-1 and nuclear factor-кB in KCs. Added with TGF-β antibodyto KC-conditioned medium reduced HSC expression of collagen I, TIMP1, and CTGF/CCN2, whereas the STAT3 inhibitor significantly decreased TGF-β1 expression in KCs. In conclusion, Leptin mediates HSC activation and hepatic fibrosis mainly through actions on KC. Particularly, TGF-β1 is a major mediator of these effects.



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