Xie Yuan, Tian Ying, Huang Junting, Deng Wanying, Li Xiaohui, Liu Yujia, Liu Hao, Gao Lei, Xie Qiu, Yu Qi
Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital (Dongdan Campus), No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China.
Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Int J Biol Sci. 2025 May 21;21(8):3505-3526. doi: 10.7150/ijbs.104778. eCollection 2025.
Polycystic ovary syndrome (PCOS) is a reproductive endocrine disease characterized by metabolic abnormalities, with 34-70% of patients with PCOS also presenting non-alcoholic fatty liver disease (NAFLD). Metformin is a first-line treatment for relieving insulin resistance in PCOS; however, the potential therapeutic application of metformin for preventing NAFLD/metabolic dysfunction-associated fatty liver disease (MAFLD) in PCOS remains under-explored. Here, we investigated the potential protective effects and the underlying mechanisms of metformin against hepatic lipid metabolic disorders in prenatal anti-Müllerian hormone (PAMH)-induced PCOS mice. First, we developed a prenatal AMH-induced PCOS-like model using pregnant C57BL/6N mice. Female offspring of mice were then subjected to the glucose tolerance test and insulin tolerance test pre- and post-treatment with metformin. H&E staining, serum hormone, and biochemical analyses were performed to determine the effects of metformin on metabolic abnormalities and liver damage in the PCOS-like model. To verify the specific mechanism of action of metformin, dehydroepiandrosterone (DHEA) and free fatty acids (FFAs; palmitic acid and oleic acid) induced alpha mouse liver 12 (AML-12) cells were used to establish a mouse liver cell model of adipose-like degeneration and lipid deposition. Metformin effectively alleviated hepatic lipid accumulation in the PCOS mice. Furthermore, mitochondrial dysfunction and loss of redox homeostasis in the liver of PCOS mice were rescued upon metformin administration. Mechanistic insights reveal that metformin regulates mitochondrial autophagy in PCOS liver tissue via the activation of the Ethe1/Keap1/Nrf2/PINK1/Parkin pathway, thereby improving liver recovery in PCOS mice. Our findings highlight the role and mechanism of metformin in ameliorating abnormal mitophagy and lipid metabolic disorders in the PCOS mice livers and the potential of metformin for addressing NAFLD in PCOS mice.
多囊卵巢综合征（PCOS）是一种以代谢异常为特征的生殖内分泌疾病，34%至70%的PCOS患者同时患有非酒精性脂肪性肝病（NAFLD）。二甲双胍是缓解PCOS患者胰岛素抵抗的一线治疗药物；然而，二甲双胍在预防PCOS患者发生NAFLD/代谢功能障碍相关脂肪性肝病（MAFLD）方面的潜在治疗应用仍有待探索。在此，我们研究了二甲双胍对产前抗苗勒管激素（PAMH）诱导的PCOS小鼠肝脏脂质代谢紊乱的潜在保护作用及其潜在机制。首先，我们使用怀孕的C57BL/6N小鼠建立了产前AMH诱导的PCOS样模型。然后，对小鼠的雌性后代在二甲双胍治疗前后进行葡萄糖耐量试验和胰岛素耐量试验。进行苏木精-伊红（H&E）染色、血清激素和生化分析，以确定二甲双胍对PCOS样模型中代谢异常和肝损伤的影响。为了验证二甲双胍的具体作用机制，使用脱氢表雄酮（DHEA）和游离脂肪酸（FFA；棕榈酸和油酸）诱导的α小鼠肝脏12（AML-12）细胞建立脂肪样变性和脂质沉积的小鼠肝细胞模型。二甲双胍有效减轻了PCOS小鼠的肝脏脂质积累。此外，给予二甲双胍后，PCOS小鼠肝脏中的线粒体功能障碍和氧化还原稳态丧失得到了挽救。机制研究表明，二甲双胍通过激活Ethe1/Keap1/Nrf2/PINK1/Parkin途径调节PCOS肝组织中的线粒体自噬，从而改善PCOS小鼠的肝脏恢复。我们的研究结果突出了二甲双胍在改善PCOS小鼠肝脏异常线粒体自噬和脂质代谢紊乱中的作用和机制，以及二甲双胍在解决PCOS小鼠NAFLD方面的潜力。
