肝脏甘油激酶在脂代谢稳态维持及脂代谢紊乱疾病中的作用及机制研究

高脂血症和脂肪肝的发病机制尚不完全清楚。肝脏是脂代谢的重要器官。肝脏甘油激酶(Gyk)通过催化甘油生成3-磷酸甘油而参与甘油三酯合成。我们预实验发现Gyk在高脂饮食诱导的肥胖小鼠肝脏表达升高，敲低Gyk显著降低小鼠的高血脂、减轻脂肪肝；降低脂合成转录因子SREBP1c及其下游脂肪酸从头合成和甘油三酯合成相关酶的表达；在正常小鼠肝脏敲低Gyk也降低SREBP1c及其靶基因表达，这些结果提示肝脏Gyk在生理性脂代谢调控及脂代谢紊乱疾病中发挥重要作用，Gyk不仅是催化甘油代谢的酶，还可能是脂代谢调控因子。本课题拟：（1）探讨肝脏Gyk在生理性脂稳态维持中的作用及其调控脂合成的新机制；（2）探讨脂代谢紊乱模型小鼠肝脏Gyk升高的原因及机制；（3）探讨肝脏Gyk在高脂饮食导致的高血脂和脂肪肝中的作用。本研究不仅能揭示Gyk调控脂代谢的新机制，而且有可能为高脂饮食导致的高血脂、脂肪肝的治疗提供新靶标。

The underlying mechanisms of hyperlipidemia and hepatic steatosis are not fully understood. Liver plays an important role in lipid metabolism. Hepatic glycerol kinase (Gyk) is involved in triglyceride synthesis through converting glycerol to glycerol-3-phoaphate. Our preliminary results showed that the expression of Gyk in liver is increased in high-fat diet induced obese mice. Knockdown of hepatic Gyk in these mice alleviated hyperlipidemia and hepatic steatosis, reduced the mRNA levels of lipogenic transcription factor SREBP1c and its target genes involved in de novo lipogenesis and triglyceride synthesis. Knockdown of hepatic Gyk in normal mice also reduced the expression of SREBP1c and its target genes. These results indicate that Gyk plays important roles in regulating lipid metabolism under physiological condition and contributes to lipid abnormalities under pathological condition. Gyk is not only an enzyme to catalyze glycerol, but also may be a regulator of lipid metabolism. In this project, we plan:(1) to investigate the new mechanism underlying the regulation of lipid metabolism by Gyk and its contribution to lipid homeostasis;(2) to identify the regulator of hepatic Gyk expression in high-fat diet induced obese mice and explore the underlying mechanisms; (3) to investigate the contribution of hepatic Gyk to high fat-diet induced hyperlipidemia and hepatic steatosis. Our study will reveal novel mechanisms involved in the homeostatic control and dysregulation of lipid metabolism by hepatic Gyk, and provide potential therapeutic target against high-fat diet induced hyperlipidemia and hepatic steatosis.