Menin通过PPARalpha调节肝脏甘油三酯代谢的分子机制

Fatty liver, characterized by the aberrant accumulation of triglycerides in hepatocytes, is strongly associated with nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhoisis and eventually hepatocellular carcinoma . Here, we describe that the impaired hepatic expression of menin, the product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, represents a common feature of several fatty liver mouse models. Indeed, the liver specific ablation of MEN1 gene expression in healthy mice induced hepatic steatosis under high-fat dietary conditions. At the molecular level, we found that menin acts synergistically with the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha to control the genes expression of fatty acid oxidation. Collectively, these data suggest a crucial role for menin as an integrator of the complex transcriptional network controlling hepatic steatosis. However, the molecular biological mechanism of the regulation of PPARalpha by menin is not yet completely clear. Based on these original discoveries, we will further mapping the interaction domain of between menin and PPARalpha by immunoprecipitation and GST-pull down assays; we will infect mice with truncated menin adenovirus which could not interact with PPARalpha to observe its effect on liver lipid metabolism. We will also knockdown PPARalpha to detect its impact on fatty acid oxidation gene expression mediated by menin. Our work is expected to elucidating the molecular mechanisms of menin / PPARalpha signaling pathway in the regulation of lipid metabolism in the liver, to provide a theoretical basis for clinical treatment and prevention of fatty liver.

脂肪肝的主要特征是肝细胞内甘油三酯过量堆积。我们前期研究发现，多种脂肪肝小鼠模型中抑癌基因menin表达显著下调。我们将小鼠肝中menin的表达沉默后，其肝内甘油三酯沉积，呈明显脂肪肝病理表现。我们又发现menin同核受体PPARalpha相互作用，调控甘油三酯的氧化。因此认为menin对于肝脏的脂代谢起着至关重要的作用。但menin调控PPARalpha的具体分子生物学机制还不完全清楚。本项目将在前期基础上通过免疫沉淀和GST-pull down等方法明确menin和PPARalpha相互作用的结构域；构建不能和PPARalpha相互作用作用的menin截短体腺病毒并观察其对小鼠肝脏脂代谢的影响；敲除PPARalpha来检测其对menin导致脂肪酸氧化相关基因表达的影响。我们的工作将有望阐明menin/PPARalpha信号通路在调控肝脏脂代谢的分子机制，为临床上防治脂肪肝提供理论基础。

Menin,即编码的基因MEN1,最初在神经内分泌肿瘤中被确定。 先前研究显示Menin增强PPARa 活性防止肝脏中甘油三酯积累。 因此我们进一步探索Menin蛋白在肝脂肪变性的作用。 我们研究发现瞬时转染化验证明Menin抑制核受体肝X受体的转录活动(LXRa)。 因此,Menin过表达导致LXRa目标基因的表达减少,如脂肪生成的酶包括SREBP-1c FASN和SCD-1。 共同免疫沉淀实验显示Menin和LXRa之间的相互作用。 总的来说,我们的数据表明,Menin作为新型LXRa阻遏物具有负调节肝脂肪生成功能。