Department of Orthopedics, Shanghai Pudong New Area People's Hospital, Shanghai, 201299, China.
Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China.
Cell Death Dis. 2023 Feb 3;14(2):82. doi: 10.1038/s41419-023-05623-4.
Metformin is the biguanide of hepatic insulin sensitizer for patients with non-alcohol fatty liver disease (NAFLD). Findings regarding its efficacy in restoring blood lipids and liver histology have been contradictory. In this study, we explore metformin's preventive effects on NAFLD in leptin-insensitive individuals. We used liver tissue, serum exosomes and isolated hepatocytes from high-fat diet (HFD)-induced Zucker diabetic fatty (ZDF) rats and leptin receptor (Lepr) knockout rats to investigate the correlation between hepatic Lepr defective and liver damage caused by metformin. Through immunostaining, RT-PCR and glucose uptake monitoring, we showed that metformin treatment activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream cytochrome C oxidase (CCO). This leads to overactivation of glucose catabolism-related genes, excessive energy repertoire consumption, and subsequent hepatocyte pyroptosis. Single-cell RNA sequencing further confirmed the hyper-activation of glucose catabolism after metformin treatment. Altogether, we showed that functional Lepr is necessary for metformin treatment to be effective, and that long-term metformin treatment might promote NAFLD progression in leptin-insensitive individuals. This provides important insight into the clinical application of metformin.
二甲双胍是治疗非酒精性脂肪性肝病（NAFLD）患者的肝胰岛素增敏剂。关于其在恢复血脂和肝脏组织学方面疗效的研究结果一直存在争议。在这项研究中，我们探讨了二甲双胍在瘦素不敏感个体中预防 NAFLD 的作用。我们使用高脂肪饮食（HFD）诱导的 Zucker 糖尿病肥胖（ZDF）大鼠和瘦素受体（Lepr）敲除大鼠的肝组织、血清外泌体和分离的肝细胞，来研究肝 Lepr 缺陷与二甲双胍引起的肝损伤之间的相关性。通过免疫染色、RT-PCR 和葡萄糖摄取监测，我们表明二甲双胍治疗激活了 AMP 激活的蛋白激酶（AMPK）及其下游细胞色素 C 氧化酶（CCO）。这导致与葡萄糖分解代谢相关的基因过度激活、能量储备过度消耗，随后发生肝细胞焦亡。单细胞 RNA 测序进一步证实了二甲双胍治疗后葡萄糖分解代谢的过度激活。总之，我们表明功能性 Lepr 对于二甲双胍治疗的有效性是必要的，长期的二甲双胍治疗可能会促进瘦素不敏感个体中 NAFLD 的进展。这为二甲双胍的临床应用提供了重要的见解。
