College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China.
Department of Nutrition and Health, China Agricultural University, Haidian, Beijing 100193, China.
Int J Biol Sci. 2023 Jul 31;19(12):3937-3950. doi: 10.7150/ijbs.85883. eCollection 2023.
Ferroptosis, an iron-dependent cell death form, has recently been observed in the development of non-alcoholic fatty liver disease (NAFLD). Melatonin (Mel) shows potential benefits for preventing and treating liver diseases. Whether and how Mel ameliorates hepatic ferroptosis in NAFLD is not fully understood. Here we established a mouse model of NAFLD induced by long-term high-fat diet (HFD) feeding. We found that Mel treatment ameliorated global metabolic abnormalities and inhibited the progression of NAFLD in mice. Most importantly, Mel supplementation significantly improved HFD-induced iron homeostasis disorders in the liver, including iron overload and ferritin transport disorders. For another, Mel ameliorated HFD-induced hepatic lipid peroxidation. The recuperative role of exogenous Mel on hepatocyte ferroptosis was also observed in PA- or Erastin-treated HepG2 cells. Mechanistically, MT2, but not MT1, was involved in the effect of Mel. Furthermore, Mel treatment inhibited HFD or Erastin-activated ER stress and activated the PKA/IRE1 signaling pathway. Co-expression of p-PKA and p-IRE1 was enhanced by the MT2 antagonist. Inhibitions of PKA and IRE1 respectively improved hepatocyte ferroptosis, and activations of cAMP/PKA reversed Mel's effect on ferroptosis. Collectively, these findings suggest that exogenous Mel inhibits hepatic ferroptosis in NAFLD by ameliorating ER stress through the MT2/cAMP/PKA/IRE1 pathway, proving that Mel is a promising candidate drug for the treatment of hepatic ferroptosis in NAFLD.
铁死亡是一种依赖铁的细胞死亡形式，最近在非酒精性脂肪性肝病 (NAFLD) 的发展中被观察到。褪黑素 (Mel) 在预防和治疗肝脏疾病方面显示出潜在的益处。Mel 是否以及如何改善 NAFLD 中的肝铁死亡尚不完全清楚。在这里，我们建立了一种由长期高脂肪饮食 (HFD) 喂养诱导的 NAFLD 小鼠模型。我们发现 Mel 治疗改善了小鼠的整体代谢异常，并抑制了 NAFLD 的进展。最重要的是，Mel 补充显著改善了 HFD 诱导的肝脏铁稳态紊乱，包括铁过载和铁蛋白转运紊乱。另一方面，Mel 改善了 HFD 诱导的肝脂质过氧化。在外源 Mel 对 PA 或 Erastin 处理的 HepG2 细胞中铁细胞铁死亡的恢复作用也得到了观察。从机制上讲，MT2 而不是 MT1 参与了 Mel 的作用。此外，Mel 处理抑制了 HFD 或 Erastin 激活的 ER 应激并激活了 PKA/IRE1 信号通路。MT2 拮抗剂增强了 p-PKA 和 p-IRE1 的共表达。PKA 和 IRE1 的抑制分别改善了肝细胞铁死亡，而 cAMP/PKA 的激活逆转了 Mel 对铁死亡的作用。总之，这些发现表明，外源性 Mel 通过改善 MT2/cAMP/PKA/IRE1 通路抑制 ER 应激来抑制 NAFLD 中的肝铁死亡，证明 Mel 是治疗 NAFLD 中肝铁死亡的有前途的候选药物。
