HSD17B13剪接变异体通过调节视黄醇代谢和脂滴稳态影响代谢性肝病进展的机制研究

代谢性肝病逐渐成为肝癌的重要病因，其遗传易感性引人关注。课题组揭示脂滴蛋白HSD17B13的剪接变异体（rs72613567:TA）对代谢性肝病及其导致的肝癌具有保护作用，但目前对其参与肝病肝癌发展机制的探索尚不足。已知HSD17B13具有视黄醇脱氢酶的活性，预实验发现HSD17B13基因型与肝病患者视黄醇代谢相关；体外实验提示脂滴在突变型肝星状细胞内聚集。综上，推测HSD17B13突变体通过调控视黄醇代谢分布及脂滴稳态影响肝病的进展。本项目拟从“人群-细胞-分子”层面展开：①验证不同基因型患者中视黄醇代谢通路的差异表达；②构建肝细胞及肝星状细胞共培养模型，探索不同基因型HSD17B13对视黄醇代谢及脂滴稳态的调节；③验证突变体的互作用蛋白，探索其参与炎症-纤维化-癌变进程的具体分子机制。本项目的实施将为HSD17B13阻止肝病进展的机制提供初步思路，并为治疗靶点的探索提供理论依据。

Metabolic liver disease is emerging as an important cause of liver cancer, and its genetic susceptibility is of interest. Lipid droplets (LD) are dynamic lipid reservoirs and are involved in cell signaling. Our group revealed that the truncated isoform (rs72613567: TA) of HSD17B13, a LD-related protein, has a protective effect on metabolic liver disease and hepatocellular carcinoma (HCC), but the mechanisms involved remain to be determined. HSD17B13 is reported to have retinol dehydrogenase activity. Preliminary experiments reveal that HSD17B13 genotype is associated with retinol metabolism in patients with liver disease; in vitro experiments suggest that LDs accumulate in hepatic stellate cells carrying mutant HSD17B13. Taken together, we hypothesize that the mutant HSD17B13 impacts the progression of liver disease and development of HCC by regulating retinol metabolism, distribution and LD homeostasis. In the project, our goals are as following: (1) to validate the differential expression of proteins related to retinol metabolic pathways in patients with different genotypes; (2) to verify the regulation of retinol metabolism and LD homeostasis by different HSD17B13 genotypes in co-culture model of hepatocyte and hepatic stellate cell; (3) to validate proteins specifically interacting with mutant HSD17B13；and eventually to uncover the molecular mechanisms involved in the progression from inflammation to fibrosis and to carcinoma. This project will provide preliminary ideas on the mechanism of HSD17B13 to prevent the progression of liver disease and provide a theoretical basis for HSD17B13 being a therapeutic target.