氯吡格雷通过上调mARC1逆转脂肪肝的作用及其机制研究

脂肪肝影响全球约1/4的人口，严重危害人类健康和生命。预实验发现：氯吡格雷能显著上调mARC1表达水平，增加NO生成，降低TMAO浓度，减轻高脂食物（HFD）饲养小鼠肝细胞内甘油三酯和脂质堆积，逆转HFD引发的肝脏AMPK抑制。据此提出假说：mARC1/NO/AMPK信号通路参与了氯吡格雷防治脂肪肝的作用。本课题拟采用HFD饲养小鼠、油酸/棕榈酸诱导肝细胞脂肪变性、mARC1基因敲降等研究手段，结合多种工具药，全面探寻mARC1、NO、AMPK、mTORC1和TMAO等在脂肪肝模型中的作用，进而细化其各种调控机制，解析其中关键药物靶标的重要性。本课题将深入揭示氯吡格雷对mARC1/NO/AMPK通路和TMAO的作用及其机理，为未来氯吡格雷治疗脂肪肝病人提供科学依据。

Metabolic-associated fatty liver disease (also known as MAFLD, formerly NAFLD) could affect 25% of the global population. The risk of steatohepatitis, fibrosis, cirrhosis, or hepatic cellular cancer would be dramatically increased due to lack of approved drugs. In an earlier pilot study, we observed that clopidogrel significantly attenuated the intracellular accumulation of lipids and triglyceride (TG) of the liver of mice fed with high-fat diet (HFD) through enhanced generation of nitric oxide (NO) and reversal of down-regulation of mARC1 and AMPK. It was hypothesized that clopidogrel could prevent and treat fatty liver through up-regulation of mARC1/NO/AMPK signaling pathways. In the studies to come, we will use HFD-fed mice, mARC1-RNAi knocked down mice, oleate/palmitate-treated Hepa 1-6 cells, and those with inactivation of hepatic pan-P450s by ABT (1-aminobenzotriazole) to further dissect the effects of mARC1, NO, sGC/cGMP, AMPK, mTORC1, TMAO, and hepatic P450s on clopidogrel-treated fatty liver by use of specific tool drugs and the underlying mechanisms. In clinical studies, we will explore use of clopidogrel to treat patients diagnosed with fatty liver and seek the biomarkers to predict its efficacy. In sum, this research project will reveal that clopidogrel could prevent and treat fatty liver via up-regulation of mARC1/NO/AMPK and AMPK/mTORC1 signaling pathways, providing novel insight into use of clopidogrel for fatty liver in humans.