Shandong University of Traditional Chinese Medicine, Jinan 250013, China; Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100032, China.
Huanggang Hospital of Chinese Medicine, Affiliated to Hubei University of Chinese Medicine, Huanggang 438000, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jan;1870(1):159570. doi: 10.1016/j.bbalip.2024.159570. Epub 2024 Oct 23.
Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.
非酒精性脂肪性肝病（NAFLD）正在成为全球公共卫生负担，但显著缺乏有效的治疗策略。根据新的研究，NAFLD 的发展可能是由线粒体功能障碍介导的。从植物来源的物质中产生线粒体调节剂来治疗线粒体功能障碍是治疗 NAFLD 的一种有吸引力的方法。橙皮苷（HES）是一种天然存在的类黄酮，是黄烷酮家族的成员。本研究旨在阐明 HES 预防高脂肪饮食（HFD）诱导的 NAFLD 的机制。评估 HFD 诱导的 NAFLD 斯普拉格-道利（SD）大鼠的血清和肝脏生化参数、肝组织学、脂质谱和线粒体功能。HES 治疗显著降低了体重增加、肝重和肝指数，同时改善了 NAFLD 大鼠的肝脂肪变性、脂质代谢紊乱和线粒体功能障碍。使用 Western blot 和实时定量聚合酶链反应（RT-qPCR）研究并证实了该机制。我们表明，在 NAFLD 大鼠的肝脏中，HES 通过 AMP 激活的蛋白激酶α（AMPKα）依赖性机制降低了动力相关蛋白 1（Drp1）、磷酸化 Drp1 丝氨酸 616（Drp1-pS616）和诱导的磷酸化 Drp1 丝氨酸 637（Drp1-pS637）、PTEN 诱导的激酶 1（PINK1）和 E3 泛素-蛋白连接酶 Parkin（Parkin）的表达。此外，HES 增加了线粒体融合蛋白线粒体融合蛋白 2（Mfn2）和视神经萎缩 1（Opa1）的表达，同时抑制了分裂蛋白 1（Fis1）的表达。在这项工作中，我们确定了 HES 预防 NAFLD 发展的独特机制。HES 可能是治疗 NAFLD 的一种有吸引力的潜在治疗剂。
