肝X受体参与CEPT1介导的足细胞脂质代谢过程及其在足细胞损伤中的机制研究

足细胞损伤是糖尿病肾病（DKD）发生发展的中心环节，足细胞内脂质代谢与其功能密切相关，因此寻找调节足细胞脂代谢的关键分子可能为DKD防治寻找到可行靶点。我们前期研究发现肝X受体β（LXRβ）可通过抑制足细胞自噬导致足细胞功能紊乱，加重DKD进展，但其对足细胞脂代谢的作用尚不明确。采用脂质组学技术我们发现在DKD小鼠足细胞中，敲低LXRβ可明显降低DKD引起的甘油酯类蓄积，并初步验证可能与LXRβ负向调控甘油酯类代谢基因CEPT1有关。因此我们推测LXRβ可通过CEPT1调控足细胞脂代谢，从而调节足细胞功能。本研究拟构建DKD小鼠模型，并构建足细胞特异性敲除LXRβ模型，明确LXRβ在生理和疾病状态下对足细胞脂代谢、功能和肾功能的影响，并在体外培养的足细胞系中初步阐明LXRβ通过CEPT1调控脂质代谢的分子机制。该研究将为阐明足细胞损伤机制提供新的视角，也为DKD寻找一个理想的干预靶点。

Podocyte plays a key role in the development of diabetic kidney disease (DKD). The lipid metabolism in podocyte is closely related to podocyte function. Therefore, it is urgent and also important to identify molecular targets related to podocyte lipid metabolism. Our previous study demonstrated that the activation of liver X receptors (LXRs), especially LXRβ, was involved in regulating the autophagy flux and affected the functions of podocyte and kidney, which was mainly regulated by AMPK and SIRT1 signaling pathways. However, the role of LXRβ that plays in the lipid metabolism in podocyte has not been clarified. By applying tissue-specific lipidomics, we found that in podocyte obtained from DKD mice, knock-down of LXRβ was associated with lower level of neutral lipids, including triglycerides and diacylglycerides. Moreover, we discovered that CEPT1, a gene regulating the biosynthesis of phospholipids from diacylglycerides, might be involved in this process. Based on our previous findings, we hypothesize that LXRβ may regulate podocyte lipid metabolism through mediating CEPT1. In this current study, we will use streptozotocin (STZ) + high fat diet (HFD) to generate DKD mice model. Then, we will use Cre-LoxP system to establish podocyte-specific LXRβ knock-out mice model, to further elucidate the effects of LXRβ on regulating podocyte lipid metabolism, podocyte function and kidney function, under both physiological and pathological conditions. Moreover, we will dig deep into the molecular mechanisms through which LXRβ regulates lipid metabolism in podocyte. This study will not only provide a new perspective for the pathogenesis of podocyte injury, but also offer rationale for the development of novel drugs for the treatment of DKD.