CSE/H2S通过激活核受体FXR缓解非酒精性脂肪肝的机制研究

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects of adults and an increasing number of children in developed countries. Nonalcoholic. fatty liver disease as a typical characteristics of different kinds metabolic syndrome.As the third gasotransmitter discovered after nitric oxide and carbon monoxide, hydrogen sulfide is an intermediate metabolic product of sulfur-containing amino acid and Sulfhydration of many kinds of protein,and hydrogen sulfide can alleviate nonalcoholic fatty liver disease through various pathway. Bile acid receptor (Farnesoid X Receptor, FXR) is an essential metabolic nuclear receptor in non-alcohol fatty liver disease. Its activation could inhibit lipogenesis and glucogenesis, decrease plasma triglycerides, increase HDL and alleviate nonalcoholic fatty liver disease. Our preliminary results suggest that hydrogen sulfide is is strongly associated with FXR and FXR target gene further influence lipogenesis and glucose metabolism. But it is not clear how endogenous hydrogen sulfide involved in FXR pathway in the fatty liver disease induced by high fat diet. Therefor,we using the high-fat diet induced NAFLD mice model, aim to investigate the role of FXR in hydrogen sulfide protection of non-alcohol fatty liver disease. We expect that this study could be able to provides a theoretical basis for the prevention and treatment of non-alcoholic fatty liver disease.

非酒精性脂肪肝在发展中国家成人和儿童中发病率呈迅速增长态势，并且是多种代谢综合征的代表性特征。硫化氢是继一氧化氮、一氧化碳之后发现的第三种气体信号分子，是体内含硫氨基酸半胱氨酸代谢的产物，能对多种蛋白产生硫氢化修饰，而且硫化氢可通过多种途径缓解非酒精性脂肪肝。肝脏胆汁酸受体FXR激活后可以抑制肝脏糖、脂代谢，降低血浆甘油三酯，升高血浆HDL并缓解脂肪肝。我们的前期实验结果提示，硫化氢很有可能通过FXR调节其下游相关靶基因表达进一步影响糖脂代谢。但内源性硫化氢是如何通过FXR参与高脂饮食诱导的脂肪肝的发病尚不清楚。本课题在高脂饮食小鼠制备的脂肪肝模型上，以代谢性核受体FXR为切入点，探讨硫化氢通过FXR而缓解脂肪肝的分子机制,为非酒精性脂肪肝的防治提供理论依据。

研究背景和目的: 硫化氢(H2S)在非酒精性脂肪性肝病中起保护作用。然而胱硫氨酸γ裂解酶(CSE)作为肝细胞中最主要的H2S生成酶，是否在NAFLD的发病机制中起作用目前尚不清楚。方法和结果:在高脂饮食(HFD)诱导的NAFLD小鼠或油酸诱导的肝细胞模型中CSE/H2S下调。为了证明CSE在NAFLD的调控作用，我们制备了肝细胞特异性CSE基因敲除小鼠(CSELKO)。与CSEloxp对照小鼠相比，给CSELKO小鼠喂食HFD，它们肝脏脂质沉积更严重，脂肪酸从头合成途径活性增加，肝脏胰岛素抵抗增加，肝脏糖异生能力更高。相比之下，H2S供体处理则缓解了这些表型变化。此外，H2S通过法尼醇X受体(FXR)对肝脏的保护作用，敲低FXR后保护作用消失。CSE/H2S促进FXR在Cys138/141位点的翻译后修饰(硫氢化修饰) ，从而增强其活性以调节与脂质和葡萄糖代谢，炎症和纤维化相关的靶基因的表达。患者肝脏中的硫氢化蛋白质组学也支持上述CSELKO小鼠中发现的CSE/H2S调控作用。结论和意义:FXR硫氢化作用是受肝脏内源性CSE/H2S影响的翻译后修饰，可能促进FXR活性，减轻NAFLD。肝脏CSE缺乏促进非酒精性脂肪性肝炎的发生。H2S与FXR之间的相互作用有望用于非酒精性脂肪肝的治疗药物研发。