神经酰胺介导细胞自噬失衡促进非酒精性脂肪性肝炎的机制研究

Nonalcoholic steatohepatitis (NASH) is the severe type of nonalcoholic fatty liver disease. Ceramide is reported to be related to insulin resistance and oxidative stress, which associate to the pathogenesis of NASH. Ceramide is highly involved in mediating two opposing autophagic pathways (cytoprotective and lethal autophagy), autophagy paradox. Our research group previously conducted a lipidomic study and reported that there was increased serum ceramide in biopsy-proven NASH patients. Further we identified the inhibition of ceramide synthesis by myriocin had attenuated high fat diet induced NASH and resumed the impaired autophagy function. We thus assume that ceramide mediates the imbalance of autophagy paradox and promotes nonalcoholic steatohepatitis. This study is intended to prove the imbalance of autophagy paradox is involved in the pathogenesis of NASH in vitro and vivo. We attempt to explore inhibition of ceramide by myriocin could attenuated NASH through regulating the autophagy paradox. Further, identifying the mechanism of autophagic regulation by ceramide in NASH. The implementation of the study is expected to provide new ideas for the pathogenesis exploration and the drug development for NASH.

非酒精性脂肪性肝炎(nonalcoholic steatohepatitis，NASH)是非酒精性脂肪性肝病的严重类型。神经酰胺通过介导胰岛素抵抗和氧化应激参与NASH的进展，同时神经酰胺亦参与两种对立的自噬通路的调节。申请人前期研究证实，神经酰胺在肝活检证实的NASH患者血清中显著升高，且进一步通过体内实验发现神经酰胺抑制剂多球壳菌素可改善高脂饮食诱导小鼠NASH严重程度，并可改善肝细胞自噬功能。故我们提出假设，神经酰胺可介导细胞保护性和致死性自噬的失衡促进NASH的发展。本课题拟通过体内外实验研究NASH的发生发展存在保护性自噬以及致死性自噬调节失衡；并探究多球壳菌素抑制神经酰胺合成对自噬失衡的调节作用以及对NASH的干预效果；进一步探索神经酰胺介导自噬失衡的分子机制的具体通路。该课题的实施有望为NASH发病机制的探讨和新药研发提供新思路。

非酒精性脂肪性肝炎(nonalcoholic steatohepatitis，NASH)是非酒精性脂肪性肝病的严重类型。神经酰胺通过介导胰岛素抵抗和氧化应激参与NASH的进展，同时神经酰胺亦参与两种对立的自噬通路的调节。该课题研究发现神经酰胺在肝活检证实的NASH患者血清中显著升高，我们动态了研究了高脂肪高胆固醇饮食诱导的小鼠从 NAFL至NASH发生发展过程中肝脏自噬动态水平变化，发现在NASH发展过程中存在自噬减弱。采用神经酰胺从头合成抑制剂(多球壳菌素)在高脂饮食诱导的NASH小鼠中的可有效缓解HFD诱导的肝脏脂肪变、炎症、脂代谢，氧化应激、凋亡等，并且对NASH小鼠肝脏受损的自噬功能有恢复作用，并进一步进行转录组学的探索分析并筛选了致死性自噬以及保护性自噬的变化，发现NASH中存在致死性自噬通路上调（Dram1,Rab7b,Hk2,Dcn,Olr1,Lkk2,Lampt5,mitf）以及保护性自噬通路下调（Ppp1r1b，Gls2,Rac3）这一自噬失衡的表现，且该自噬失衡可被多球壳菌素的治疗逆转。结合体外实验结果，多球壳菌素抑制神经酰胺合成对NASH的干预作用确实部分通过自噬通路介导。该课题的实施有望为NASH发病机制的探讨和新药研发提供新思路。