Expression of leptin receptors in hepatic sinusoidal cells.
Expression of leptin receptors in hepatic sinusoidal cells.
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DOI：
10.1186/1476-5926-2-s1-s12
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发表时间：
2004-01-14
期刊：
影响因子：
--
通讯作者：
Sato N
中科院分区：
文献类型：
--
作者：
Ikejima K;Lang T;Zhang YJ;Yamashina S;Honda H;Yoshikawa M;Hirose M;Enomoto N;Kitamura T;Takei Y;Sato N
新出现的证据表明，瘦素在肝脏炎症和纤维化中起着关键作用，然而，瘦素在肝脏中促纤维化作用的确切机制尚未得到很好的阐明。因此，本研究旨在探讨瘦素受体（Ob-R）在肝窦细胞中的表达和功能。采用原位胶原酶灌注法分离大鼠肝脏中的肝星状细胞（hsc）、库普弗细胞（Kupffer cells）和窦状内皮细胞（SECs），采用RT-PCR技术分别检测Ob-Ra和Ob-Rb、Ob-R短、长亚型的表达。Ob-Ra mRNA在hsc和sec中普遍存在。相比之下，Ob-Rb仅在SECs和Kupffer细胞中检测到，而在培养7 d的hsc中未检测到。事实上，在瘦素孵育1小时后，在SECs中观察到STAT-3的酪氨酸磷酸化，Ob-Rb信号的下游事件，但在hsc中没有观察到。此外，瘦素增加了Kupffer细胞和SECs中AP-1 DNA结合活性和tgf - β 1 mRNA水平，而瘦素未能增加hsc中tgf - β 1 mRNA水平。这些发现表明SECs和Kupffer细胞，而不是hsc，表达功能性瘦素受体，瘦素通过该受体诱导tgf - β 1的产生。因此，我们假设瘦素由脂肪细胞全系统产生，局部由hsc产生，可上调tgf - β 1，从而促进正弦微环境下的组织修复和纤维形成。
Emerging evidence has suggested a critical role of leptin in hepatic inflammation and fibrogenesis, however, the precise mechanisms underlying the profibrogenic action of leptin in the liver has not been well elucidated. Therefore, the present study was designed to investigate the expression and functions of leptin receptors (Ob-R) in hepatic sinusoidal cells. Hepatic stellate cells (HSCs), Kupffer cells and sinusoidal endothelial cells (SECs) were isolated from rat livers by in situ collagenase perfusion followed by differential centrifugation technique, and expression of Ob-Ra and Ob-Rb, short and long Ob-R isoforms, respectively, were analyzed by RT-PCR. Ob-Ra mRNA was detected ubiquitously in HSCs and SECs. In contrast, Ob-Rb was detected clearly only in SECs and Kupffer cells, but not in 7-day cultured HSCs. Indeed, tyrosine-phosphorylation of STAT-3, a downstream event of Ob-Rb signaling, was observed in SECs, but not in HSCs, 1 hr after incubation with leptin. Further, leptin increased AP-1 DNA binding activity and TGF-beta 1 mRNA levels in Kupffer cells and SECs, whereas leptin failed to increase TGF-beta 1 mRNA in HSCs. These findings indicated that SECs and Kupffer cells, but not HSCs, express functional leptin receptors, through which leptin elicits production of TGF-beta 1. It is hypothesized therefore that leptin, produced systemically from adipocytes and locally from HSCs, up-regulates TGF-beta 1 thereby facilitate tissue repairing and fibrogenesis in the sinusoidal microenvironment.