GCK突变调控ATGL/CEPT1表达在改善糖尿病肝脏脂质代谢异常中的作用及机制研究

GCK基因突变导致的青少年发病的成人型糖尿病2型(GCK-MODY)具有在高血糖情况下保持低心脑血管并发症风险的特点。我们前期临床血清脂质组学研究发现GCK-MODY患者的脂解酶ATGL/CEPT1在HDLs上的高表达促进中性脂质分解产生PCps，构成该疾病动脉粥样硬化保护特性的基础。GCK基因主要表达于血脂代谢的关键器官肝脏，但是GCK突变介导的ATGL/CEPT1表达在肝脏脂质代谢中的具体作用机制仍未完全阐明。据报道PPARα的激活与ATGL/CEPT1的表达密切相关，因此我们提出科学假说，肝脏GCK突变可以激活PPARα促进脂解酶的合成，进而改善血脂代谢和减少心血管并发症。本课题拟通过临床样本、GCK突变的肝细胞和小鼠模型，验证GCK突变对肝脏细胞脂代谢的影响，是否通过PPARα通路发挥调控作用，有助于阐明高血糖状态下心血管保护作用的分子机制，对糖尿病并发症的早防早治具有重要意义。

Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a kind of special diabetes characterized with low occurrence (lower than T2DM patients and similar to healthy control subjects) of microvascular and macrovascular complications under prolonged hyperglycemia. In our previous study, we found that enhanced recruitment of ATGL (adipose triglyceride lipase)/CEPT1 (choline/ethanolamine phosphotransferase 1) onto HDLs and resultant increases in the production of HDL-PCps from neutral lipids such as TAGs and DAGs essentially underlie the atheroprotective profiles associated with GCK-MODY due to mutation in the GCK gene. GCK is mainly expressed in the liver closely associated with lipid metabolism, the mechanism of GCK mutation induced enhanced expression of ATGL/CEPT1 in liver lipid metabolism is not clear. It has been reported that activation of PPARα is closely related with the expression of ATGL/CEPT1. Therefore, we propose that GCK mutation in liver enhance the expression of ATGL/CEPT1 to improve the lipid metabolism and reduce vascular complications through stimulation of PPARα signaling pathway. This study is based on clinical samples, human hepatocyte and mouse model to explore whether the beneficial effect of GCK mutation on liver lipid metabolism is through PPARα stimulation. It is expected to illustrate the molecular mechanism underlie the protection of GCK-MODY patients from vascular complications despite chronic exposure to hyperglycemia, and provide new idea and target for prevention and treatment of vascular complications in diabetes.