Yasuda Yoichi, Shimizu Masahito, Sakai Hiroyasu, Iwasa Junpei, Kubota Masaya, Adachi Seiji, Osawa Yosuke, Tsurumi Hisashi, Hara Yukihiko, Moriwaki Hisataka
Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Chem Biol Interact. 2009 Dec 10;182(2-3):159-64. doi: 10.1016/j.cbi.2009.07.015. Epub 2009 Jul 30.
Hepatic fibrosis is a major complication of various chronic liver diseases. Activated hepatic stellate cells (HSCs) play a critical role in the development of liver fibrosis and the axis of platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR), a member of receptor tyrosine kinases (RTKs), is closely associated with the activation of HSC. Insulin-like growth factor (IGF)-1 receptor (IGF-1R), which also belongs to RTKs, interacts with the PDGF/PDGFR axis, thereby cooperatively promoting hepatic fibrosis. We herein examined the effects of (-)-epigallocatechin gallate (EGCG), which inhibits the activation of several types of RTKs, on the development of rat liver fibrosis induced by carbon tetrachloride (CCl4). Drinking water with 0.1% EGCG significantly decreased the serum levels of both aspartate aminotransferase and alanine aminotransferase raised by CCl4, thus indicating an improvement of liver injury. In CCl4-injected rats, EGCG markedly attenuated hepatic fibrosis and decreased the amount of hydroxyproline in the experimental liver. The expression of PDGFRbeta and IGF-1R mRNAs in the liver was significantly lowered by the treatment with EGCG. EGCG also decreased the expression of PDGFRbeta and alpha-smooth muscle actin proteins, thus indicating the inhibition of HSC activation. These findings suggest that EGCG can exert, at least in part, an anti-fibrotic effect on the liver by targeting PDGFRbeta and IGF-1R. EGCG might therefore be useful in both the prevention and treatment of hepatic fibrosis.
肝纤维化是各种慢性肝病的主要并发症。活化的肝星状细胞（HSC）在肝纤维化的发展中起关键作用，血小板衍生生长因子（PDGF）/PDGF受体（PDGFR）轴作为受体酪氨酸激酶（RTK）的一员，与HSC的活化密切相关。胰岛素样生长因子（IGF）-1受体（IGF-1R）也属于RTK，它与PDGF/PDGFR轴相互作用，从而协同促进肝纤维化。我们在此研究了抑制多种类型RTK活化的（-）-表没食子儿茶素没食子酸酯（EGCG）对四氯化碳（CCl4）诱导的大鼠肝纤维化发展的影响。饮用含0.1%EGCG的水可显著降低CCl4升高的天冬氨酸转氨酶和丙氨酸转氨酶的血清水平，从而表明肝损伤有所改善。在注射CCl4的大鼠中，EGCG明显减轻了肝纤维化，并降低了实验肝脏中羟脯氨酸的含量。EGCG处理可显著降低肝脏中PDGFRβ和IGF-1R mRNA的表达。EGCG还降低了PDGFRβ和α-平滑肌肌动蛋白的蛋白表达，从而表明对HSC活化的抑制作用。这些发现表明，EGCG至少可以通过靶向PDGFRβ和IGF-1R对肝脏发挥抗纤维化作用。因此，EGCG可能对肝纤维化的预防和治疗都有用。
