Selenium Ameliorated Oxidized Fish Oil-Induced Lipotoxicity via the Inhibition of Mitochondrial Oxidative Stress, Remodeling of Usp4-Mediated Deubiquitination, and Stabilization of Ppar alpha

文献类型： 外文期刊

第一作者： Zhang, Dian-Guang

作者： Zhang, Dian-Guang;Lei, Xi-Jun;Zhao, Tao;Xu, Yi-Chuang;Wei, Xiao-Lei;Lv, Wu-Hong;Luo, Zhi;Kunz, Wolfram S. S.;Kunz, Wolfram S. S.;Zito, Ester;Zito, Ester;Luo, Zhi;Luo, Zhi

作者机构：

关键词： oxidized fish oil; selenium; mitochondrial oxidative stress; lipid metabolism; ubiquitination modification

期刊名称：ANTIOXIDANTS & REDOX SIGNALING （ 影响因子：6.6； 五年影响因子：8.2 ）

ISSN： 1523-0864

年卷期： 2023 年

页码：

收录情况： SCI

摘要： Aims: 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 via the inhibition of oxidative stress and determine its potential mechanism. Results: 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 (Ppar alpha) and ubiquitin-specific protease 4 (Usp4) protein expression. High Se supplementation also alleviated OFO-induced reduction of thioredoxin reductase 2 (txnrd2) messenger RNA (mRNA) expression level and activity. The txnrd2 knockdown experiments revealed that txnrd2 mediated Se- and oxidized eicosapentaenoic acid (oxEPA)-induced changes of mitochondrial reactive oxygen species (mtROS) and further altered Usp4 mediated-deubiquitination and stabilization of Ppar alpha, which, in turn, modulated mitochondrial fatty acid beta-oxidation and metabolism. Mechanistically, Usp4 deubiquitinated Ppar alpha and ubiquitin-proteasome-mediated Ppar alpha degradation contributed to oxidative stress-induced mitochondrial dysfunction. Innovation: These findings uncovered a previously unknown mechanism by which Se and OFO interacted to affect lipid metabolism via the Txnrd2-mtROS-Usp4-Ppar alpha pathway, which provides the new target for NAFLD prevention and treatment.Conclusion: Se ameliorated OFO-induced lipotoxicity via the inhibition of mitochondrial oxidative stress, remodeling of Usp4-mediated deubiquitination, and stabilization of Ppar alpha.

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