蛋白酶hepsin 在调节肝脏糖与脂代谢中的功能研究

The liver plays an important role in regulating metabolic homeostasis. Dysregulated liver function may lead to common metabolic diseases such as hyperlipidemia, obesity and diabetes, thereby increasing the risk of cardiovascular diseases such as stroke, myocardial infarction and heart failure. Hepsin is a type II transmembrane serine protease highly expressed in the liver. To date, the physiological function of hepsin in the liver remains unknown. Our preliminary studies indicate that hepsin may activate hepatocyte growth factor (HGF) in the liver and stimulate the HGF down-stream pathway, thereby promoting hepatic glycogen and lipid synthesis. Hepsin knockout mice had low levels of blood glucose and liver glycogen and were resistant to high-fat diet-induced obesity and fatty liver. In this project, we plan to conduct biochemical, cell biology and mouse model studies to elucidate the function of hepsin in the liver. Our studies should help to identify new molecular mechanisms in regulating glucose and lipid metabolism in the liver and to understand the role of such mechanisms in hyperlipidemia, obesity and diabetes. Such studies should be of great importance for the prevention and treatment of major cardiovascular and metabolic diseases.

肝脏是维持代谢平衡的一个重要器官。肝脏功能失调可诱发高血脂、肥胖、糖尿病等常见代谢疾病，并增加心血管疾病如中风、心肌梗死和心力衰竭发生的危险性。Hepsin是一种在肝脏中高表达的II型跨膜丝氨酸蛋白酶，迄今其生理功能仍然不清楚。我们的前期研究表明，hepsin 能够在肝脏通过活化肝细胞生长因子 (hepatocyte growth factor)，激活其下游分子通路，从而促进肝糖原和脂质合成。Hepsin 敲除小鼠血糖和肝糖原水平降低，并且有抗高脂饮食导致肥胖和脂肪肝的表型。本研究将通过生物化学、细胞生物学和小鼠模型实验来揭示hepsin在肝脏中的功能。本项研究将有助于揭示调控肝脏葡萄糖和脂类代谢稳态调控的新分子机理，以及该机理失常在高血脂、肥胖、糖尿病等代谢疾病中的作用。我们的研究对重大心血管和代谢性疾病的防治有重要意义。

肝脏是维持代谢平衡的一个重要器官。肝脏功能失调可诱发高血脂、肥胖、糖尿病等常见代谢疾病，并增加心血管疾病如中风、心肌梗死和心力衰竭发生的危险性。Hepsin是一种在肝脏中高表达的II型跨膜丝氨酸蛋白酶，迄今其生理功能仍然不清楚。.通过本项目的研究，我们发现hepsin基因敲除小鼠的血糖、血脂和肝糖原水平较低，脂肪组织棕色化和基础代谢率增加，能够抵抗高脂饮食导致的肥胖、高血糖和高脂血症。我们还发现hepsin作用的分子机制，即活化肝细胞生长因子(hepatocyte growth factor，HGF)，激活其下游的Met信号通路，促进肝脏糖原和脂质合成。Hepsin缺乏则使HGF生成减少，导致肝糖原和脂质减少。此外，我们还揭示了hepsin在肝细胞中酶原活化的机制，以及糖基化对hepsin在细胞内运输与活化中的重要作用。这些数据表明，hepsin是肝脏代谢和能量平衡的关键调节因子，提示hepsin有望成为治疗肥胖和糖尿病的新靶点。我们在hepsin酶原活化和细胞转运研究中的发现，对研究其它跨膜蛋白酶的细胞生物学机理也有重要的指导意义。