Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
Free Radic Biol Med. 2023 Jul;203:69-85. doi: 10.1016/j.freeradbiomed.2023.04.001. Epub 2023 Apr 10.
Adiponectin receptor 2 (AdipoR2) can be activated by its endogenous ligand adiponectin to reduce hepatic steatosis, and is regarded as a therapeutic target for metabolic associated fatty liver disease (MAFLD). This study proposes a novel anthraquinone compound, emodin succinate monoethyl ester (ESME), which activates AdipoR2, inhibits hepatic lipogenesis, promotes fatty acid oxidation, and alleviates experimental hepatic steatosis in hamsters and mice. Molecular docking shows that ESME has strong binding potential with AdipoR2 by forming a arene-arene interaction. AdipoR2 on the cytomembrane of HepG2 cells can be labeled by fluorescent ESME (Cy5-ESME). ESME activates AdipoR2, AMPK and PPARα, and reduces lipid deposition in palmitic acid or oleic acid-induced HepG2 and L02 cells. Suppression of AdipoR2 expression or AMPK activation completely eliminates the effect of ESME on reducing lipid accumulation in hepatocytes. Oral administration of ESME reduces liver lipid production and accumulation, and alleviates hepatic steatosis in hamsters and Apoe mice induced by high-fat diet. Compared with statins and emodin, ESME showed prepotent efficacy and safety in reducing hepatic steatosis and protecting hepatocytes. Furthermore, ESME activates CaMKK2 and LKB1 in liver to activate AMPK and reduce lipogenesis through stimulating AdipoR2. Taken together, ESME reduces hepatic lipid accumulation and alleviates hepatic steatosis by agonizing AdipoR2. ESME is a promising new agent for clinical treatment of MAFLD.
脂联素受体 2（AdipoR2）可以被其内源性配体脂联素激活，从而减少肝脂肪变性，被认为是代谢相关脂肪性肝病（MAFLD）的治疗靶点。本研究提出了一种新型蒽醌化合物，琥珀酸单乙酯（ESME），它可以激活 AdipoR2，抑制肝内脂质生成，促进脂肪酸氧化，减轻仓鼠和小鼠的实验性肝脂肪变性。分子对接表明，ESME 通过形成芳环-芳环相互作用，与 AdipoR2 具有很强的结合潜力。HepG2 细胞的细胞质膜上的 AdipoR2 可以被荧光 ESME（Cy5-ESME）标记。ESME 可以激活 AdipoR2、AMPK 和 PPARα，并减少棕榈酸或油酸诱导的 HepG2 和 L02 细胞中的脂质沉积。抑制 AdipoR2 表达或 AMPK 激活完全消除了 ESME 对减少肝细胞中脂质积累的作用。ESME 口服给药可减少肝脏脂质生成和积累，并减轻高脂肪饮食诱导的仓鼠和 Apoe 小鼠的肝脂肪变性。与他汀类药物和大黄素相比，ESME 在降低肝脂肪变性和保护肝细胞方面表现出更强的疗效和安全性。此外，ESME 通过刺激 AdipoR2 激活 CaMKK2 和 LKB1 在肝脏中激活 AMPK 并减少脂肪生成。综上所述，ESME 通过激动 AdipoR2 减少肝脏脂质堆积并缓解肝脂肪变性。ESME 是治疗 MAFLD 的一种很有前途的新型药物。
