<em>Mig-6</em> Plays a Critical Role in the Regulation of Cholesterol Homeostasis and Bile Acid Synthesis

The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.胆固醇稳态（cholesterol homeostasis）的破坏会导致胆固醇水平升高，进而引发心血管疾病。丝裂原诱导基因6（Mitogen Inducible Gene 6, Mig-6）是一类即刻早期反应基因，可被多种丝裂原、应激刺激及激素诱导表达。为明确Mig-6在肝脏中的代谢调控功能，本研究利用白蛋白-Cre小鼠模型（Albumin-Cre）对小鼠肝脏中的Mig-6进行条件性敲除，具体基因型为Albcre/+Mig-6f/f; Mig-6d/d。结果显示，Mig-6条件性敲除（Mig-6d/d）小鼠表现出肝脏肿大与脂肪肝表型；其血清总胆固醇、低密度脂蛋白胆固醇（LDL）、高密度脂蛋白胆固醇（HDL）水平及肝内脂质含量均显著升高，每日粪便胆汁酸排泄量则显著降低。对该类小鼠肝脏提取的mRNA进行DNA微阵列（DNA microarray）分析发现，调控脂质代谢、胆汁酸及胆固醇合成的基因表达发生显著改变，而调控胆汁酸胆道排泄与甘油三酯合成的基因表达与Mig-6f/f野生型对照小鼠无明显差异。上述研究结果表明，Mig-6在胆固醇稳态维持及胆汁酸合成过程中发挥关键调控作用。肝脏特异性条件性敲除Mig-6的小鼠可出现肝脏肿大与肝内脂质积累增加，为探究胆固醇稳态及胆汁酸合成调控相关的遗传与分子事件提供了全新的模型体系。阐明Mig-6调控胆固醇稳态的分子机制，将为开发更高效的心血管疾病防治策略提供新的理论依据。