Functional analysis of novel feeding response gene that directed at anti-obesity

肝脏X受体(LXR)α和LXRβ属于核受体超家族，在脂质代谢的转录控制中起核心作用。我们描述了一种新的LXR靶点，midline-1相互作用的g12样蛋白（MIG12），最近被鉴定为乙酰辅酶a羧化酶结合蛋白。这种结合通过激活乙酰辅酶A羧化酶（一种重新合成脂肪酸的限速酶）诱导重新合成脂肪酸（FA）。利用MIG12基因启动子对荧光素酶报告基因进行分析，发现存在lxr响应元件（LXRE）和碳水化合物响应元件（ChREBP）响应元件，分别命名为LXRE3和碳水化合物响应元件1。LXRE3和碳水化合物响应元件1的缺失和突变分别使LXR和ChREBP的响应性丧失。电泳迁移率转移实验表明LXR/类视黄醇X受体α复合物与LXRE3结合。高糖处理导致ChREBP激活或LXR激活剂刺激大鼠原代肝细胞中MIG12表达，联合处理进一步刺激MIG12表达。此外，再喂可诱导小鼠肝脏表达MIG12。MIG12的过表达刺激了LXR配体刺激的FA合成和甘油三酯积累，而MIG12的下调则减弱了LXR配体刺激的FA合成和甘油三酯积累。这些结果表明，MIG12是肝脏中LXR激活刺激脂肪生成的介质。

Liver X receptor(LXR)αand LXRβbelong to the nuclear receptor superfamily and play central roles in the transcriptional control of lipid metabolism. We describe a novel LXR target, midline-1-interacting G12-like protein(MIG12), which has been recently identified as an acetyl-coenzyme A carboxylase-binding protein. The binding causes the induction of de novo fatty acid(FA) synthesis through the activation of acetyl-coenzyme A carboxylase(a rate-limiting enzyme for de novo FA synthesis). Luciferase reporter gene assays using the MIG12 gene promoter revealed the existence of a LXR-responsive element(LXRE) and carbohydrate-responsive element-binding protein(ChREBP)-responsive element named LXRE3 and carbohydrate response element 1, respectively. Deletion and mutation of LXRE3 and carbohydrate response element 1 abolished LXR and ChREBP responsiveness, respectively. Electrophoretic mobility shift assays demonstrated that the LXR/retinoid X receptorαcomplex was bound to LXRE3. Treatment with high glucose concentration, which leads ChREBP activation, or LXR activator stimulated MIG12 expression in rat primary hepatocytes, and combined treatment further stimulated MIG12 expression. Furthermore, hepatic expression of MIG12 in mice was induced by refeeding. Overexpression of MIG12 stimulated and knockdown of MIG12 attenuated LXR ligand-stimulated de novo FA synthesis and triacylglycerol accumulation. These results indicate that MIG12 is a mediator for stimulation of lipogenesis by LXR activation in the liver.