Shenzhen Institute of Nutrition and Health, Fishery College, Huazhong Agricultural University, Wuhan, China.
Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
Antioxid Redox Signal. 2024 Mar;40(7-9):433-452. doi: 10.1089/ars.2022.0194. Epub 2023 Jul 6.
Studies demonstrated that oxidized fish oil (OFO) promoted oxidative stress and induced mitochondrial dysfunction and lipotoxicity, which attenuated beneficial effects of fish oil supplements in the treatment of nonalcoholic fatty liver disease (NAFLD). The current study was performed on yellow catfish, a good model to study NAFLD, and its hepatocytes to explore whether selenium (Se) could alleviate OFO-induced lipotoxicity the inhibition of oxidative stress and determine its potential mechanism. The analysis of triglycerides content, oxidative stress parameters, and histological and transmission electronic microscopy observation showed that high dietary Se supplementation alleviated OFO-induced lipotoxicity, oxidative stress, and mitochondrial injury and dysfunction. RNA-sequencing and immunoblotting analysis indicated that high dietary Se reduced OFO-induced decline of peroxisome-proliferator-activated receptor alpha (Pparα) and ubiquitin-specific protease 4 (Usp4) protein expression. High Se supplementation also alleviated OFO-induced reduction of thioredoxin reductase 2 () messenger RNA (mRNA) expression level and activity. The knockdown experiments revealed that mediated Se- and oxidized eicosapentaenoic acid (oxEPA)-induced changes of mitochondrial reactive oxygen species (mtROS) and further altered Usp4 mediated-deubiquitination and stabilization of Pparα, which, in turn, modulated mitochondrial fatty acid β-oxidation and metabolism. Mechanistically, Usp4 deubiquitinated Pparα and ubiquitin-proteasome-mediated Pparα degradation contributed to oxidative stress-induced mitochondrial dysfunction. These findings uncovered a previously unknown mechanism by which Se and OFO interacted to affect lipid metabolism the Txnrd2-mtROS-Usp4-Pparα pathway, which provides the new target for NAFLD prevention and treatment. Se ameliorated OFO-induced lipotoxicity the inhibition of mitochondrial oxidative stress, remodeling of Usp4-mediated deubiquitination, and stabilization of Pparα. 40, 433-452.
研究表明，氧化鱼油（OFO）会促进氧化应激，导致线粒体功能障碍和脂毒性，从而减弱鱼油补充剂在治疗非酒精性脂肪肝病（NAFLD）方面的有益作用。本研究以黄颡鱼为模型，研究其肝细胞，以探讨硒（Se）是否能减轻 OFO 诱导的脂毒性、抑制氧化应激，并确定其潜在机制。分析甘油三酯含量、氧化应激参数、组织学和透射电子显微镜观察结果表明，高膳食 Se 补充可减轻 OFO 诱导的脂毒性、氧化应激、线粒体损伤和功能障碍。RNA 测序和免疫印迹分析表明，高膳食 Se 降低了 OFO 诱导的过氧化物酶体增殖物激活受体α（Pparα）和泛素特异性蛋白酶 4（Usp4）蛋白表达下降。高 Se 补充还减轻了 OFO 诱导的硫氧还蛋白还原酶 2 () 信使 RNA（mRNA）表达水平和活性降低。基因敲低实验表明， 介导了 Se 和氧化二十碳五烯酸（oxEPA）诱导的线粒体活性氧（mtROS）变化，并进一步改变了 Usp4 介导的 Pparα去泛素化和稳定，从而调节线粒体脂肪酸β氧化和代谢。从机制上讲，Usp4 去泛素化 Pparα和泛素-蛋白酶体介导的 Pparα降解导致氧化应激诱导的线粒体功能障碍。这些发现揭示了一个以前未知的机制，即 Se 和 OFO 相互作用影响脂质代谢和 Txnrd2-mtROS-Usp4-Pparα 通路，为 NAFLD 的预防和治疗提供了新的靶点。Se 减轻了 OFO 诱导的脂毒性、抑制了线粒体氧化应激、重塑了 Usp4 介导的去泛素化作用，并稳定了 Pparα。 40, 433-452.
