Tomita Kengo, Azuma Toshifumi, Kitamura Naoto, Nishida Jiro, Tamiya Gen, Oka Akira, Inokuchi Sayaka, Nishimura Takeshi, Suematsu Makoto, Ishii Hiromasa
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Gastroenterology. 2004 Mar;126(3):873-85. doi: 10.1053/j.gastro.2003.12.008.
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.
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.
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 (SCD). 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.
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.
脂肪变性的治疗对于预防酒精性肝病中纤维化的发展至关重要。本研究旨在检验吡格列酮（一种作为过氧化物酶体增殖物激活受体γ（PPARγ）配体的抗糖尿病药物）是否能预防酒精性脂肪肝。
给喂食含乙醇液体饲料的大鼠每天经胃内给予10mg/kg该药物，持续6周。通过转录组分析挖掘参与该药物作用的肝脏基因，并通过实时聚合酶链反应和蛋白质免疫印迹分析确认其变化。还在体外评估了吡格列酮对原代培养肝细胞的直接作用。
吡格列酮显著减轻了慢性乙醇暴露引起的脂肪变性和脂质过氧化，而未改变胰岛素抵抗。该药物改善作用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（SCD）上调。吡格列酮对c-Met信号通路的这种作用源于其酪氨酸磷酸化以及由此导致的载脂蛋白B（apoB）介导的通过极低密度脂蛋白（VLDL）从肝细胞动员脂质的上调，以及固醇调节元件结合蛋白（SREBP）-1c和SCD水平的下调和肝脏中甘油三酯合成的减少。
吡格列酮激活c-Met和依赖VLDL的脂质回收，并抑制甘油三酯合成，从而作为减轻乙醇诱导的肝脏脂肪变性的潜在有用策略。
