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PRDX6 Promotes Fatty Acid Oxidation via PLA2-Dependent PPARα Activation in Rats Fed High-Fat Diet

过氧化物酶体 非酒精性脂肪肝 β氧化 脂肪生成 内科学 脂肪变性 内分泌学 脂肪肝 分解代谢 肉碱 化学 过氧化物酶体增殖物激活受体 脂质代谢 生物化学 生物 受体 新陈代谢 医学 疾病
作者
Wen Zen Shen,Lin Yang,Yi Yang,Peng Wang,Xiaofang Tao,Yujun Shen,Sheng Wang,Yujun Shen
出处
期刊:Antioxidants & Redox Signaling [Mary Ann Liebert, Inc.]
卷期号:38 (16-18): 1184-1200 被引量:4
标识
DOI:10.1089/ars.2022.0065
摘要

Aims: Nonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally, which is defined as an excess accumulation of fat caused by the imbalance of lipogenesis and lipid catabolism. Recently, increasing evidence suggests that peroxiredoxin 6 (PRDX6) is involved in the pathogenesis and progression of NAFLD. However, little is known regarding its role in liver lipid catabolism. Results: We found that PRDX6 level was significantly increased in liver tissues after high-fat diet (HFD) treatment. PRDX6 knockout (KO) exacerbated HFD-induced hepatic steatosis. PRDX6 KO did not affect messenger RNA (mRNA) and protein levels of peroxisome proliferator-activated receptor alpha (PPARα). However, PRDX6 KO decreased the mRNA and protein levels of carnitine palmitoyltransferase-1alpha (CPT-1α) and acyl-CoA oxidase 1 (ACOX1), the target genes of PPARα. PRDX6 KO also did not activate AMP-activated protein kinase (AMPK)α/proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), the upstream signal of PPARα. However, PRDX6 KO reduces the levels of PPARα activators, the oxidized fatty acids (9- and 13-hydroxyoctadecadienoic acid) in HFD rats. More interestingly, PRDX6 promoted the production of oxidized fatty acids by hydrolyzing oxidized low-density lipoprotein (Ox-LDL), which depends on its phospholipase A2 (PLA2) activity. PRDX6 mutation on its PLA2 and its competitive phospholipase inhibitor inhibited the production of the oxidized fatty acids as well as the activation of PPARα. Furthermore, PRDX6 overexpression enhanced the transcriptional activation of PPARα. Innovation and Conclusion: This study elucidates for the first time the role of PLA2 enzyme activity of PRDX6 in fatty acid oxidation and reveals a novel mechanism of PRDX6 involved in liver steatosis. Antioxid. Redox Signal. 38, 1184-1200.
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