Kupffer cells mediate leptin-induced liver fibrosis.
Kupffer cells mediate leptin-induced liver fibrosis.
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DOI：
10.1053/j.gastro.2009.04.011
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发表时间：
2009-08
期刊：
影响因子：
29.4
通讯作者：
George J
中科院分区：
文献类型：
--
作者：
Wang J;Leclercq I;Brymora JM;Xu N;Ramezani-Moghadam M;London RM;Brigstock D;George J
瘦素在肝脏中具有促纤维化作用，尽管这一过程的机制尚不清楚。我们试图阐明瘦素对肝星状细胞（HSC）的直接和间接影响。从 Sprague-Dawley 大鼠中分离的 HSC 暴露于瘦素；通过定量PCR评估胶原蛋白-I、基质金属蛋白酶组织抑制剂-1 (TIMP1)、转化生长因子β1 (TGFβ1)和结缔组织生长因子(CTGF/CCN2)的表达。在 HSC 中评估了与瘦素一起孵育后库普弗细胞 (KC) 和窦内皮细胞 (SEC) 的培养基的影响；分析了 α-平滑肌肌动蛋白 (αSMA) 的产生和 KC 信号传导。与瘦素一起孵育不会激活 HSC。然而，使用来自与瘦素一起孵育的 KC 的培养基培养的 HSC 增加了编码促纤维形成因子 I 型胶原蛋白、TIMP1、TGFβ1 和 CTGF/CCN2 的基因表达，以及 αSMA 蛋白水平和增殖。这些效应是瘦素受体依赖性的，因为从瘦素受体缺陷的 Zucker (fa/fa) 大鼠中分离出的 KC 的条件培养基不会激活 HSC。在用瘦素孵育的 KC 中，TGFβ1 和 CTGF/CCN2 的 mRNA 和蛋白表达增加。瘦素增强了 KC 中 STAT3、AKT 和 ERK1/2 的磷酸化，并增加了 AP-1 和 NF-κB DNA 结合。最后，在 KC 条件培养基中添加抗 TGFβ 会抑制 HSC 胶原蛋白 I、TIMP1 和 CTGF/CCN2 的表达，而 STAT3 抑制剂则减弱 KC 产生 TGFβ1。瘦素通过间接影响 KC 介导 HSC 活化和肝纤维化；这些作用部分是由 TGFβ1 介导的。
Leptin has pro-fibrogenic 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 isolated from Sprague-Dawley rats were exposed to leptin; expression of collagen-I, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF/CCN2) was assessed by quantitative PCR. The effects of medium from Kupffer cells (KCs) and sinusoidal endothelial cells (SECs) following incubation with leptin were evaluated in HSCs; α-smooth muscle actin (αSMA) production and KC signaling were analyzed. HSCs were not activated by incubation with leptin. However, HSCs cultured with medium taken from KCs that had been incubated with leptin increased expression of genes that encode the pro-fibrogenic factors collagen I, TIMP1, TGFβ1and CTGF/CCN2, as well as αSMA protein levels and proliferation. These effects were leptin-receptor dependent, because conditioned medium from KCs that were isolated from leptin receptor-deficient Zucker (fa/fa) rats did not activate HSCs. In KCs incubated with leptin, mRNA and protein expression of TGFβ1 and CTGF/CCN2 increased. Leptin potentiated STAT3, AKT and ERK1/2 phosphorylation in KCs and increased AP-1 and NF-κB DNA binding. Finally, addition of anti-TGFβ to KC-conditioned medium inhibited HSC expression of collagen I, TIMP1 and CTGF/CCN2, whereas a STAT3 inhibitor attenuated TGFβ1 production by KC. Leptin mediates HSC activation and liver fibrosis through indirect effects on KC; these effects are partly mediated by TGFβ1.
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DOI：
10.1152/ajpheart.00928.2007
发表时间：
2007-12-01
影响因子：
4.8
作者：
Cortez, Dolores M.;Feldman, Marc D.;Chandrasekar, Bysani
通讯作者：
Chandrasekar, Bysani
影响因子：
19.6
作者：
Disthabanchong, S.;Radinahamed, P.;Rajatanavin, R.
通讯作者：
Rajatanavin, R.
影响因子：
4.8
作者：
Cao, Q;Mak, KM;Lieber, CS
通讯作者：
Lieber, CS
影响因子：
4.8
作者：
Han, YP;Zhou, L;Tsukamoto, H
通讯作者：
Tsukamoto, H
DOI：
10.1073/pnas.96.22.12719
发表时间：
1999-10-26
影响因子：
11.1
作者：
George, J;Roulot, D;Bissell, DM
通讯作者：
Bissell, DM