我国有超过两亿的脂肪肝病人。目前我们对脂肪肝发生机制的研究主要集中在脂肪酸的从头合成（de novo lipogenesis）。然而人体的脂肪从头合成能力极低（约为每天2~5克），不能完全解释当前肥胖和脂肪肝的大范围流行。我们设想碳水化合物饮食能通过不依赖于脂肪从头合成的途径增加肝脏脂肪的积累。三碳代谢物如甘油醛，甘油三磷酸和二羟基丙酮酸既是糖酵解的产物，又为甘油三酯和各种磷脂的合成提供甘油三磷酸和烷基甘油磷酸的碳架。因此，三碳代谢物可能是偶联糖酵解和脂肪合成通路的重要分子。本项目拟研究两种位于不同代谢通路的三碳激酶（糖酵解通路的三碳糖激酶和脂降解通路的甘油激酶），通过比较它们的酶学特性和调控方式，构建目的基因功能缺失和功能获得性的细胞和小鼠模型，结合代谢组、脂肪组和代谢建模，阐明三碳激酶参与肝脏代谢流调控，特别是三碳糖激酶介导糖脂偶联促进脂肪积累的机制，为脂肪肝的治疗提供新的药物靶点。

Fatty liver disease affects more than 200 million patients in China. Current research in the field of fatty liver disease is primarily focused on mechanisms of de novo lipogenesis. However, the very limited capacity of de novo lipogenesis in human can not fully account for the wide prevalence of fatty liver disease, especially under the condition of low fat/high carbohydrate diet. C3 metabolites (e.g. glycerolaldehyde, dihydroxyacetone-3-phosphate) are derived from glycolysis pathways and serve as precursors for glycerol lipid synthesis. Therefore, we hypothesized that C3 metabolites may serve as a coupling link between glycolysis and lipid synthesis. Here we propose to examine the enzymatic and regulatory mechanisms of glycerol kinase (GK) and triose/glyceraldehyde kinase (TK), construct cell and mouse models for gain and loss-of-function studies, and examine their role in hepatic metabolic flux control and hepatic lipid accumulation. Through these work, we hope to identify novel mechanisms of hepatic lipid accumulation, and provide novel drug targets for the treatment of fatty liver disease.