Geraniol上调Kupffer细胞中PPARγ的表达防止急性肝功能衰竭的分子机制研究

急性肝功能衰竭(ALF)是多种因素引起的大量肝细胞坏死及严重肝功能损害。Kupffer细胞是肝脏的巨噬细胞群体，通过极化成M1或是M2型，发挥促炎或抗炎双重作用。调节Kupffer细胞向M2极化，对于ALF炎性损伤的控制至关重要。我们前期实验发现，香叶醇能上调ALF模型鼠肝脏中M2细胞极化相关转录因子PPARγ的表达，抵抗ALF的发生，但机制不明。根据研究背景和预实验结果，我们提出香叶醇抵抗ALF的假设分子机制：香叶醇调节Kupffer细胞中DNA甲基化/去甲基化相关酶的表达，介导PPARγ启动子DNA去甲基化，上调PPARγ表达。同时香叶醇调节NCoR等转录抑制子的表达，促进PPARγ与NCoR复合体的结合。增强的PPARγ靶向抑制M1极化和促进M2极化，防止ALF的发生。本项目的完成有助于揭示香叶醇调节PPARγ的表达和转录活性的分子机制，为香叶醇治疗ALF提供全面的理论支持。

Acute liver failure (ALF) is a large number of liver cell necrosis and serious liver function damage caused by a variety of factors. Kupffer cells are the main macrophage population in the liver. They can polarize into M1 or M2 cells under different conditions and play a dual role in promoting inflammation and anti-inflammatory. Regulating the polarization of Kupffer cells towards M2 is essential for the control of inflammatory injury in ALF. Our previous experiments found that geraniol can significantly up-regulate the expression of the M2 polarization-related transcription factor PPARγ in the liver of ALF model mice and resist the occurrence of ALF, but the specific mechanism is unknown. Based on the existing research background and preliminary experimental results, we propose a hypothesized molecular mechanism of geraniol resisting ALF: Geranyl regulates the expression of DNA methylation/demethylation related enzymes in Kupffer cells, mediates the decrease of DNA methylation level in PPARγ promoter, and thus up-regulating the expression of PPARγ. At the same time, geraniol regulates the expression of NCoR and promotes the binding of PPARγ protein to NCoR. The increased expression and enhanced transcriptional inhibitory activity of PPARγ targeted to inhibit the M1 polarization signaling pathway, activate the M2 polarization signaling pathway, promote the polarization of M2-type Kupffer cells and the production of anti-inflammatory factors, and prevent the occurrence of ALF. The completion of this project will help to reveal the molecular mechanism of geraniol regulating PPAR γ expression and transcriptional activity, and provide a comprehensive theoretical support for the treatment of ALF by geraniol.