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

肝X受体（LXR）α和LXRβ属于核受体超家族，在脂质代谢的转录调控中发挥重要作用。我们描述了一种新的LXR靶点，中线-1相互作用的G12样蛋白（MIG 12），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（一种从头脂肪酸合成的限速酶）诱导从头脂肪酸（FA）合成。使用MIG 12基因启动子的荧光素酶报告基因测定揭示了分别命名为LXRE 3和碳水化合物响应元件1的LXR响应元件（LXRE）和碳水化合物响应元件结合蛋白（ChREBP）响应元件的存在。LXRE 3和碳水化合物反应元件1的缺失和突变分别使LXR和ChREBP的反应性消失。电泳迁移率变动分析表明LXR/维甲酸X受体α复合物与LXRE 3结合。用导致ChREBP活化的高葡萄糖浓度或LXR活化剂处理刺激大鼠原代肝细胞中的MIG 12表达，并且联合处理进一步刺激MIG 12表达。此外，通过再喂养诱导小鼠肝脏中MIG 12的表达。MIG 12的过表达刺激和MIG 12的敲低减弱LXR配体刺激的从头FA合成和三酰甘油积累。这些结果表明，MIG 12是肝脏中通过LXR活化刺激脂肪生成的介体。

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.