Wang Jianhua, Leclercq Isabelle, Brymora Joanne M, Xu Ning, Ramezani-Moghadam Mehdi, London Roslyn M, Brigstock David, George Jacob
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Westmead, Australia.
Gastroenterology. 2009 Aug;137(2):713-23. doi: 10.1053/j.gastro.2009.04.011. Epub 2009 Apr 16.
BACKGROUND & AIMS: Leptin has profibrogenic effects in liver, although the mechanisms of this process are unclear. We sought to elucidate the direct and indirect effects of leptin on hepatic stellate cells (HSCs).
HSCs from Sprague-Dawley rats were exposed to leptin and expression of collagen-I, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor beta1 (TGF-beta1), and connective tissue growth factor (CTGF/CCN2) was assessed. The effects of medium from Kupffer cells (KCs) and sinusoidal endothelial cells (SECs) following leptin were evaluated in HSCs; alpha-smooth muscle actin (alphaSMA) production and KC signaling were analyzed.
HSCs were not activated by incubation with leptin. However, HSCs cultured with medium taken from KCs that were incubated with leptin had increased expression of collagen I, TIMP1, TGF-beta1, and CTGF/CCN2, as well as alphaSMA protein levels and proliferation. These effects were leptin receptor dependent because conditioned medium from KCs isolated from leptin receptor-deficient Zucker (fa/fa) rats did not activate HSCs. In KCs incubated with leptin, messenger RNA and protein expression of TGF-beta1 and CTGF/CCN2 increased. Leptin potentiated signal transducer and activator of transcription 3, AKT, and extracellular signal-related kinase 1/2 phosphorylation in KCs and increased AP-1 and nuclear factor-kappaB DNA binding. Finally, addition of anti-TGF-beta to KC-conditioned medium inhibited HSC expression of collagen I, TIMP1, and CTGF/CCN2, whereas signal transducer and activator of transcription 3 inhibitor attenuated TGF-beta1 production by KC.
Leptin mediates HSC activation and liver fibrosis through indirect effects on KC; these effects are partly mediated by TGF-beta1.
瘦素在肝脏中具有促纤维化作用，但其作用机制尚不清楚。我们试图阐明瘦素对肝星状细胞（HSC）的直接和间接作用。
将来自Sprague-Dawley大鼠的HSC暴露于瘦素中，评估I型胶原、基质金属蛋白酶组织抑制剂-1（TIMP1）、转化生长因子β1（TGF-β1）和结缔组织生长因子（CTGF/CCN2）的表达。评估瘦素处理后库普弗细胞（KC）和窦状内皮细胞（SEC）的培养基对HSC的影响；分析α平滑肌肌动蛋白（αSMA）的产生和KC信号传导。
HSC与瘦素孵育后未被激活。然而，用与瘦素孵育的KC培养基培养的HSC，其I型胶原、TIMP1、TGF-β1和CTGF/CCN2的表达增加，αSMA蛋白水平和增殖也增加。这些作用依赖于瘦素受体，因为从瘦素受体缺陷的Zucker（fa/fa）大鼠分离的KC的条件培养基不能激活HSC。在与瘦素孵育的KC中，TGF-β1和CTGF/CCN2的信使核糖核酸和蛋白质表达增加。瘦素增强了KC中信号转导和转录激活因子3、AKT以及细胞外信号调节激酶1/2的磷酸化，并增加了AP-1和核因子κB的DNA结合。最后，向KC条件培养基中添加抗TGF-β可抑制HSC中I型胶原、TIMP1和CTGF/CCN2的表达，而信号转导和转录激活因子3抑制剂可减弱KC产生的TGF-β1。
瘦素通过对KC的间接作用介导HSC激活和肝纤维化；这些作用部分由TGF-β1介导。
