肝脏脂滴异常蓄积和脂代谢紊乱与非酒精性脂肪肝（NAFLD）的发生密切相关。申请人在前期研究中发现一个新型肝脂滴蛋白17β-HSD13在NAFLD中显著上调，且受LXR/SREBP-1c调控；肝脏过表达17β-HSD13可显著促进小鼠肝脏脂质聚集。然而，17β-HSD13在NAFLD发生发展中的作用尚不明确。本课题拟使用转基因和基因敲除小鼠及组学等分子生物学手段，进一步阐明17β-HSD13在NAFLD中的作用和机制。我们将：1）明确17β-HSD13转基因和敲除小鼠的代谢表型；2）使用反映脂肪肝不同阶段特征的动物模型（高脂、MCD和STAM模型），探讨17β-HSD13在NAFLD发生、转归中的作用；3）用脂质组和代谢组学等技术探讨17β-HSD13的酶学功能及其在调节肝脏脂质稳态中的机制。本研究的完成不仅有助于揭示NAFLD发生和发展的机制，也将为脂肪肝的防治提供新的潜在靶点。

Hepatic lipid droplet accumulation and abnormal lipid metabolism correlate tightly with NAFLD progression. Previous studies by our laboratory have reported a newly identified liver lipid droplet (LD)-associated protein-17β-HSD13 as a pathogenic molecule in the development of NAFLD through the LXR/SREBP-1c axis. Overexpression of 17β-HSD13 caused markedly accumulation of lipid in mouse liver. The molecular mechanisms by which 17β-HSD13 participates in hepatic lipid homeostasis and promotes the pathogenesis of NAFLD remains largely unknown. In the present proposal, we hypothesize that 17β-HSD13 may play a critical role in the regulation of liver lipid metabolism and its dysfunction may disrupt hepatic lipid homeostasis. Three specific aims are proposed to test the hypothesis. Specific aim 1 will define the phenotypes of 17β-HSD13 liver-specific transgenic and knockout mice; Specific aim 2 will determine the pathophysiogical role of 17β-HSD13 in the pathogenesis of NAFLD by placing both liver-specific transgenic mouse and knockout animals under high-fat diet、MCD and STAM models；Specific aim 3 will characterize the biological function of 17β-HSD13 by using biochemical, lipidomic, and metabolomic approaches. The completion of the proposed studies will not only help clarify the role of 17β-HSD13 in the pathogenesis of NALFD, but also provide a potential therapeutic target for the treatment NAFLD.