肝窦内皮细胞中的鞘糖脂合成途径对胰岛素抵抗及肝脏脂肪变的作用

Glycosphingolipids (GSLs) play an important role in insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), and inhibition the synthesis of GSLs improved obesity-induced IR and NAFLD. It is likely to represent a new strategy for the treatment of obesity-induced IR and NAFLD, but the mechanism of GSLs effect on IR is still unclear. Ceramide glucosyltransferase, an enzyme encoded by the UGCG gene, is a rate-limiting enzyme catalyzing the first step of GSLs synthesis from ceramide. A study has constructed a specific UGCG knockout mice model in the liver parenchymal cells (HCs), but it did not improve obesity-induced IR and NAFLD, suggesting that HCs was not the effective cells of IR induced by GSLs. In earlier research, we found that the genes involved in GSLs biosynthesis led by UGCG were significantly enriched in liver sinusoidal endothelial cells (LSECs). So whether LSECs is the main cell for GSLs-induced IR and NAFLD? This study aims to illustrate the molecular mechanism of UGCG and LSEC switch to regulate the occurrence and development of IR and NAFLD by controlling the GSLs biosynthesis, through a specific UGCG knockout mice model in LSECs.

鞘糖脂（GSLs）在胰岛素抵抗（IR）和肝脂变中发挥重要作用，抑制GSLs的合成改善了肥胖诱导的IR和肝脂变。很可能代表治疗由肥胖诱导的IR和非酒精性脂肪肝（NAFLD）的新策略，但GSLs对IR作用的真正途径并不清楚。神经酰胺葡糖基转移酶（Ugcg），是催化神经酰胺合成GSLs第一步反应的限速酶。有研究构建了肝实质细胞（HCs）中特异敲除Ugcg的小鼠，但并未改善肥胖诱导的IR和肝脂变。提示HCs并不是GSLs诱导IR的主要效应细胞。我们前期实验发现以Ugcg为首的GSLs合成通路中的基因在肝窦内皮细胞（LSECs)中显著富集。那么LSECs是否是GSLs诱导IR及NAFLD起始的主要细胞群？本研究拟通过特异敲除LSECs的Ugcg小鼠模型，阐明Ugcg在LSECs中通过控制GSLs合成进而调节IR和NAFLD发生发展的分子机制。探讨LSECs在IR及NAFLD发展中的开关调控作用机制。

鞘糖脂（GSLs）在胰岛素抵抗（IR）和肝脂变中发挥重要作用，抑制GSLs的合成改善了肥胖诱导的IR和肝脂变。很可能代表治疗由肥胖诱导的IR和非酒精性脂肪肝（NAFLD）的新策略，但GSLs对IR作用的真正途径并不清楚。神经酰胺葡糖基转移酶（UGCG），是催化神经酰胺合成GSLs第一步反应的限速酶。通过本项目研究发现：1）以UGCG为核心的GSLs合成途径在肝脏中是通过肝窦内皮细胞（LSECs）发挥主导作用的；2）首次发现肝脏LSECs 特异性敲除UGCG能够明显减轻肝脏脂肪变性，降低胰岛素抵抗，减缓肝脏单纯脂肪变性向脂肪性肝炎发展的进程；3）其机制主要通过对LSECs的窗孔开合及NO合成的信号通路调控，进一步导致肝内胰岛素抵抗信号通路及脂代谢紊乱，肝细胞脂肪异常堆积和一系列生理病理表型变化。本项目研究首次阐明了UGCG在LSECs中通过控制GSLs合成、LSECs的窗孔开合进而调节IR和NAFLD发生发展的分子机制，为NAFLD的预防和逆转开拓新思路和提供理论依据。