Kupffer Cells Mediate Leptin-Induced Liver Fibrosis

B IL IA R Y TR A C T ACKGROUND & AIMS: Leptin has profibrogenic efects in liver, although the mechanisms of this process re unclear. We sought to elucidate the direct and indiect effects of leptin on hepatic stellate cells (HSCs). ETHODS: HSCs from Sprague–Dawley rats were exosed to leptin and expression of collagen-I, tissue inhibtor of matrix metalloproteinases-1 (TIMP1), transformng growth factor 1 (TGF1), and connective tissue rowth factor (CTGF/CCN2) was assessed. The effects of edium from Kupffer cells (KCs) and sinusoidal endohelial cells (SECs) following leptin were evaluated in SCs; -smooth muscle actin ( SMA) production and C signaling were analyzed. RESULTS: HSCs were not ctivated by incubation with leptin. However, HSCs culured with medium taken from KCs that were incubated ith leptin had increased expression of collagen I, IMP1, TGF1, and CTGF/CCN2, as well as SMA rotein levels and proliferation. These effects were leptin eceptor dependent because conditioned medium from Cs isolated from leptin receptor-deficient Zucker (fa/fa) ats did not activate HSCs. In KCs incubated with leptin, essenger RNA and protein expression of TGF1 and TGF/CCN2 increased. Leptin potentiated signal transucer and activator of transcription 3, AKT, and extraellular signal-related kinase 1/2 phosphorylation in KCs nd increased AP-1 and nuclear factorB DNA binding. inally, addition of anti-TGFto KC-conditioned meium inhibited HSC expression of collagen I, TIMP1, and TGF/CCN2, whereas signal transducer and activator of ranscription 3 inhibitor attenuated TGF1 production y KC. CONCLUSIONS: Leptin mediates HSC activaion and liver fibrosis through indirect effects on KC; hese effects are partly mediated by TGF1.