TM6SF2基因E167K突变调控ApoB/VLDL引发肝内脂质蓄积的机制研究

非酒精性脂肪肝（NAFLD）是最常见的慢性肝病，其典型特征是肝内脂质过量蓄积。我们的前期研究及文献报道提示TM6SF2基因E167K突变降低VLDL的分泌进而引发肝内脂质过量蓄积，但其潜在分子机制尚不明确。ApoB（ApoB100、ApoB48）作为VLDL组装和分泌的关键蛋白，我们提出科学假说：TM6SF2基因E167K突变调控ApoB导致VLDL的分泌减少进而引发肝内脂质蓄积。本研究利用前期已构建的E167K敲入及肝脏、小肠TM6SF2条件性敲除小鼠及小鼠原代肝细胞与小肠上皮细胞，在人群-动物-细胞水平，深入探讨TM6SF2基因E167K突变调控ApoB/VLDL引发肝内脂质过量蓄积的分子机制，并进行功能回复验证。同时，阐明TM6SF2调控ApoB的“亚型特异性”与TM6SF2“组织特异性”的相关性。本项目为明确NAFLD的分子遗传机制及促进NAFLD的临床精准防治提供一定的理论证据。

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease. It is characterized by excessive hepatic lipid accumulation. Our previous studies and literature reports suggested that TM6SF2 gene E167K mutation may induce excessive hepatic lipid accumulation by reducing the secretion of VLDL. However, the underlying molecular mechanism remains unclear. ApoB (ApoB100, Apob48) represents the key protein for the assembly and secretion of VLDL. We propose our scientific hypothesis: TM6SF2 gene E167K mutation may reduce the secretion of VLDL through by regulating ApoB, which, in turn, induce excessive hepatic lipid accumulation. This proposed project intends to explore the molecular mechanism of TM6SF2 gene E167K mutation inducing hepatic lipid accumulation by regulating ApoB/VLDL at individual, animal, and cellular levels through by the E167K knockin mice, the conditional knockout mice models of TM6SF2 in liver and small intestine, primary hepatocytes and small intestinal epithelial cells. Meanwhile, the project will elucidate the association between the "subtype specificity" in the regulation of ApoB by TM6SF2 and the "tissue specificity" of TM6SF2. This project will provide some theoretical basis for clarifying the molecular genetic susceptibility of NAFLD and the clinical precise prevention and treatment of NAFLD.