胃激素ghrelin和nesfatin-1在肠道菌群紊乱促进非酒精性脂肪肝发生中的作用和机制

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased steadily in our country. Despite that its underlying mechanism remains unknown, gut microbiota is strongly associated with NAFLD pathogenesis, largely related to changes in lipid metabolism induced by obesity. Based on our preliminary data, we hypothesize that LPS-induced chronic inflammation may disrupt the balance regulation on the gastric hormones: ghrelin and nesfatin-1, and render the hepatocytes hypersensitive to ghrelin and resistant to nesfatin-1 in the synthesis of triglyceride, leading to the development of hepatic steatosis. The following experiments are designed to demonstrate this hypothesis: (1) to examine the role of LPS/TLR4 in the development of NAFLD;(2) to explore the mechanism by which gut microbiota regulates production of gastric hormones: ghrelin and nesfatin-1; (3) to investigate the underlying mechanism by which ghrelin and nesfatin-1 modulate lipid metabolism in the hepatocytes;(4) to examine the mechanism by which gut microbiota alters the sensitivity of hepatocytes to ghrelin and nesfatin-1; (5) to investigate the mechanism underlying the gastric bypass surgery induced improvement in NAFLD. Completion of the proposal will unravel the crucial role of ghrelin and nesfatin-1 in the development of NAFLD, and therefore provide novel therapeutic strategies targeting the TLR4 and gastric X/A like endocrine cells for the intervention of NAFLD.

非酒精性脂肪肝（NAFLD）的发生率在我国增长迅速，成为新的慢性流行病。肠道菌群紊乱在NAFLD发生中的作用及机制是一亟需解决的科学问题。我们的前期研究发现：内毒素（LPS）引起的胃激素ghrelin和nesfatin-1调节失衡及肝细胞脂代谢对这两种激素敏感性改变可能是肠道菌群紊乱影响NAFLD的重要机制。本课题拟开展以下研究验证这一假说：（1）LPS/TLR4在肠道菌群紊乱影响NAFLD中的作用；（2）肠道菌群紊乱引起ghrelin/nesfatin-1调节紊乱的机制；（3）Ghrelin/nesfatin-1调节肝脏脂代谢的机制；（4）肠道菌群紊乱导致肝脏脂代谢对ghrelin/nesfatin-1敏感性变化的机制；（5）胃旁路手术改善NAFLD的机制。本课题将阐明肠道菌群紊乱影响NAFLD的内分泌机制，为针对TLR4和胃X/A样内分泌细胞多靶点防治NAFLD的新药开发提供理论基础。

非酒精性脂肪肝（NAFLD）的发生率在我国增长迅速，成为新的慢性流行病。肠道菌群紊乱在NAFLD发生中的作用及机制是一亟需解决的科学问题。我们的课题假说是：内毒素（LPS）引起的胃激素ghrelin和nesfatin-1调节失衡及肝细胞脂代谢对这两种激素敏感性改变可能是肠道菌群紊乱影响NAFLD的重要机制。针对这一假说，我们的研究发现：（1）长期低浓度LPS是肠道菌群紊乱影响NAFLD发生发展的重要因子；其机制可能主要通过激活肝脏Kupffer细胞M1极化；（2）LPS参与肠道菌群紊乱引起ghrelin/nesfatin-1调节紊乱；（3）Ghrelin/nesfatin-1在生理条件下主要通过mTOR-PPARgamma通路调节肝实质细胞的脂质代谢，而在长期慢性低度炎症病理条件下，则通过抑制肝脏Kupffer 细胞M1极化改善非酒精性脂肪性肝炎； (4) 胃X/A样细胞内mTOR信号通路一方面通过ghrelin调节肝细胞的脂质代谢，另一方面通过nesfatin-1 调节肝细胞脂质代谢和脂肪细胞表型影响非酒精性肝病的发生发展；（5）改良胃旁路手术EDGB具有操作简单、术后并发症少、减肥改善NAFLD的效果与传统RYGB手术类似的特点。本课题发现初步阐明了肠道菌群紊乱影响NAFLD的内分泌机制，为针对胃X/A样内分泌细胞靶点防治NAFLD的新药开发提供理论基础。