Li Jiaqi, Wang Mingchao, Qu Kai, Sun Yuyao, Yin Zequn, Dong Na, Sun Xin, Xu Yitong, Chen Liang, Zhang Shuang, Xian Xunde, Xu Suowen, Ma Likun, Duan Yajun, Zhu Haibo
Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Acta Pharm Sin B. 2025 Aug;15(8):4047-4063. doi: 10.1016/j.apsb.2025.05.015. Epub 2025 May 21.
Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2',3',5'-Tri--acetyl- -(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used and mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific 1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced AAV- injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPK1/2-LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPK1-FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPK1/2-ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPK.
高胆固醇血症是动脉粥样硬化发生的重要危险因素。2',3',5'-三-O-乙酰基-β-(3-羟基苯基)腺苷（IMM-H007）是一种新型的AMPK激动剂，已在代谢性疾病中显示出保护作用。然而，其对高胆固醇血症中胆固醇和甘油三酯代谢的影响仍不清楚。在本研究中，我们旨在阐明IMM-H007调节胆固醇和甘油三酯代谢的作用及具体机制。为实现这一目标，我们使用[具体小鼠品系1]和[具体小鼠品系2]小鼠建立高胆固醇血症/动脉粥样硬化模型。此外，对肝细胞特异性AMPKα1/α2敲除小鼠进行为期5周的高胆固醇饮食以建立高胆固醇血症，同时通过腺相关病毒（AAV）注射联合16周的高胆固醇饮食诱导动脉粥样硬化。我们的结果表明，IMM-H007改善了高胆固醇血症小鼠的胆固醇和甘油三酯代谢。机制上，IMM-H007调节AMPKα1/α2-LDLR信号通路，增加肝脏中胆固醇的摄取。此外，IMM-H007激活AMPKα1-FXR通路，促进肝脏胆固醇向胆汁酸的转化。此外，IMM-H007通过激活AMPKα1/α2-ATGL通路预防肝脏脂肪变性。总之，我们的研究表明，IMM-H007是一种有前景的治疗药物，可通过激活AMPK改善高胆固醇血症和动脉粥样硬化。
