Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met
Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met
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DOI：
10.1053/j.gastro.2003.12.008
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发表时间：
2004-03-01
期刊：
影响因子：
29.4
通讯作者：
Ishii, H
中科院分区：
文献类型：
--
作者：
Tomita, K;Azuma, T;Ishii, H
背景与目的：脂肪变性的治疗对于预防酒精性肝病纤维化的发展非常重要。本研究旨在检测吡格列酮（一种抗糖尿病药物，作为过氧化物酶体增殖物激活受体γ（PPAR-gamma）的配体）是否可以预防酒精性脂肪肝。方法：用含乙醇的流质饲料喂养大鼠，每天灌胃给予本品10 mg/kg，连续6周。通过转录组分析挖掘与试剂作用相关的肝脏基因，并通过实时聚合酶链反应和蛋白质印迹分析证实其变化。还在体外评估了吡格列酮对原代培养肝细胞的直接影响。结果如下：吡格列酮显着衰减脂肪变性和脂质过氧化引起的慢性乙醇暴露，而不改变胰岛素抵抗。改善试剂效果的机制似乎涉及恢复乙醇诱导的c-Met下调和硬脂酰辅酶A去饱和酶（SCID）上调。吡格列酮对c-Met信号传导途径的这种作用是由于其酪氨酸磷酸化和由此导致的载脂蛋白B（apo B）介导的脂质从肝细胞通过极低密度脂蛋白（VLDL）动员的上调，以及固醇调节元件结合蛋白（SREBP）1c和SCD水平的下调和肝脏甘油三酯合成的减少。结论：吡格列酮激活c-Met和VLDL依赖性脂质修复并抑制甘油三酯合成，从而作为一种潜在有用的策略来减轻乙醇诱导的肝脂肪变性。
Background & Aims: Treatment of steatosis is important in preventing development of fibrosis in alcoholic liver diseases. This study aimed to examine if pioglitazone, an antidiabetic reagent serving as a ligand of peroxisome proliferator-activated receptor gamma (PPAR-gamma), could prevent alcoholic fatty liver. Methods: Rats fed with an ethanol-containing liquid diet were given the reagent at 10 mg/kg per day intragastrically for 6 weeks. Hepatic genes involved in actions of the reagent were mined by transcriptome analyses, and their changes were confirmed by real-time polymerase chain reaction and Western blotting analyses. The direct effects of pioglitazone on primary-cultured hepatocytes were also assessed in vitro. Results: Pioglitazone significantly attenuated steatosis and lipid peroxidation elicited by chronic ethanol exposure without altering insulin resistance. Mechanisms for improving effects of the reagent appeared to involve restoration of the ethanol-induced down-regulation of c-Met and up-regulation of stearoyl-CoA desaturase (SCID). Such effects of pioglitazone on the c-Met signaling pathway resulted from its tyrosine phosphorylation and resultant up-regulation of the apolipoprotein B (apoB)-mediated lipid mobilization from hepatocytes through very low-density lipoprotein (VLDL) as well as down-regulation of sterol regulatory element binding protein (SREBP) 1c and SCD levels and a decrease in triglyceride synthesis in the liver. Conclusions: Pioglitazone activates c-Met and VLDL-dependent lipid retrieval and suppresses triglyceride synthesis and thereby serves as a potentially useful stratagem to attenuate ethanol-induced hepatic steatosis.