Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats
Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats
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DOI：
10.1002/hep.21338
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发表时间：
2006-10-01
期刊：
影响因子：
13.5
通讯作者：
Fukui, Hiroshi
中科院分区：
文献类型：
--
作者：
Kitade, Mitsuteru;Yoshiji, Hitoshi;Fukui, Hiroshi
非酒精性脂肪性肝炎（NASH）可能导致纤维化、肝硬化和肝细胞癌（HCC）;然而，疾病进展的确切机制尚未完全了解。血管生成已被证明在慢性肝病的进展中起重要作用。本研究的目的是阐明血管生成在NASH肝纤维化和肝癌发生发展中的作用。Zucker大鼠，自然发展瘦素受体突变，和他们的瘦的同窝大鼠喂养胆碱缺乏，氨基酸定义的饮食。Zucker和同窝大鼠均显示出明显的脂肪性肝炎和氧化应激标志物的升高（例如，硫代巴比妥酸反应物质和8-羟基脱氧鸟苷）。与此形成鲜明对比的是，肝纤维化，谷胱甘肽-S-转移酶胎盘型（GST-P）阳性癌前病变，肝癌的发展，在同窝大鼠，但不是在Zucker大鼠。肝脏新生血管和血管内皮生长因子（VEGF），一种有效的血管生成因子的表达，只增加在同窝大鼠，几乎与纤维化和癌变平行。CD 31免疫阳性的新生血管主要位于沿着纤维化间隔或GST-P阳性病变中。我们的体外研究表明，瘦素在VEGF的存在下发挥促血管生成活性。总之，这些结果表明瘦素介导的新生血管与VEGF协调在NASH肝纤维化和肝癌发生发展中起重要作用。
Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH.