前列腺素E2受体1激活导致的Kupffer细胞极化在蛋氨酸-胆碱缺乏饮食所致非酒精性脂肪肝炎中的作用和机制

Nonalcoholic steatohepatitis (NASH) is the major determinant of hepatic fibrosis, hepatocellular carcinoma and liver failure. However, the pathological of NASH is still unclear. Prostaglandin E2 (PGE2) is an important lipid mediator of inflammation. However, the role of PGE2 and its receptor in the development of NASH remains unknown. We found that: the expression of PGE2 receptor subtype 1 (EP1) is remarkably increased both in the Methionine choline deficiency diet (MCD)-induced NASH mice and the specimens from NASH patients. EP1 deficiency significantly inhibited the progression of Methionine choline deficiency diet-induced NASH. The activation of EP1 induced the M1 polarization of Kupffer cells and the increased expression of inflammatory cytokines. The signaling pathway of EP1-β-arrestin2 could be an important factor contributed to EP1-induced M1 polarization of Kupffer cells. In addition, EP1 specific knocked out in Kupffer cells significantly inhibited the M1 polarization of kupffer cells and the apoptosis of hepatocytes. In this project, 1) We will perform the specimens from NASH patients and EP1 knockout mice to determine the mechanism that EP1 regulation of Kupffer cells. 2) We will employ EP1-β-arrestin2 knockout mice to clarify whether inhibition of EP1-β-arrestin2 in kupffer cells could improve the MCD-induced NASH. This study dedicates to provide the new target for the intervention and therapy of NASH.

非酒精性脂肪肝炎（NASH）是引起肝纤维化、肝癌和肝衰竭的重要因素，但其发病机制尚不清楚。前列腺素E2是体内重要的致炎性脂质分子，其不同受体亚型在NASH发病中的作用至今还未阐明。我们的预实验结果提示：肝脏前列腺素E2受体1（EP1）在NASH小鼠模型中和NASH患者肝脏中表达显著升高，敲除EP1后明显改善蛋氨酸-胆碱缺乏饮食诱导的非酒精性脂肪肝炎；EP1激活诱导了Kupffer细胞M1极化和炎症因子的表达增加，β-arrestin2/JNK信号通路可能介导上述作用；而敲除Kupffer细胞EP1显著抑制肝细胞凋亡。本研究计划：1）基于NASH患者临床标本和EP1受体敲除鼠，研究EP1调控Kupffer细胞极化的分子机制；2）利用肝脏EP1-β-arrestin2敲除鼠研究抑制Kupffer细胞EP1-β-arrestin2的激活能否改善NASH。此研究将为临床干预NASH提供新靶点。

非酒精性脂肪肝炎（NASH）是引起肝纤维化、肝癌和肝衰竭的重要因素，但其发病机制尚不清楚。前列腺素E2是体内重要的致炎性脂质分子，其不同受体亚型在NASH发病中的作用至今还未阐明。我们发现：肝脏前列腺素E2受体1（EP1）在NASH小鼠模型中和NASH患者肝脏中表达显著升高，敲除EP1后明显改善蛋氨酸-胆碱缺乏饮食诱导的非酒精性脂肪肝炎；EP1激活诱导了Kupffer细胞M1极化和炎症因子的表达增加并促进了肝细胞凋亡和脂质沉积，β-arrestin2/JNK1/2信号通路介导了上述作用；而抑制Kupffer细胞EP1/β-arrestin2显著改善NASH的发生。此研究将为临床干预NASH提供新靶点。