PRDX6 Promotes Fatty Acid Oxidation via PLA2-Dependent PPARα Activation in Rats Fed High-Fat Diet
- 1 June 2023
- journal article
- research article
- Published by Mary Ann Liebert Inc in Antioxidants and Redox Signaling
- Vol. 38 (16-18), 1184-1200
- https://doi.org/10.1089/ars.2022.0065
Abstract
Aims: Non-alcoholic 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 mRNA and protein levels of peroxisome proliferator-activated receptor alphaα (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 AMPKα/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.Keywords
This publication has 44 references indexed in Scilit:
- Regulation of hepatic lipin-1 by ethanol: Role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in miceJournal of Hepatology, 2011
- Overexpression of Peroxiredoxin 6 Does Not Prevent Ethanol-Mediated Oxidative Stress and May Play a Role in Hepatic Lipid AccumulationThe Journal of pharmacology and experimental therapeutics, 2009
- Oil red-O stains non-adipogenic cells: a precautionary noteCytotechnology, 2004
- Involvement of lipid peroxidation and organic peroxides in UVA-induced Matrix Metalloproteinase-1 expressionFree Radical Biology & Medicine, 2004
- CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γNature, 2003
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001
- ASSESSMENT OF DONOR FATTY LIVERS FOR LIVER TRANSPLANTATION1Transplantation, 2001
- Role for Peroxisome Proliferator-Activated Receptor α in Oxidized Phospholipid–Induced Synthesis of Monocyte Chemotactic Protein-1 and Interleukin-8 by Endothelial CellsCirculation Research, 2000
- 1-Cys Peroxiredoxin, a Bifunctional Enzyme with Glutathione Peroxidase and Phospholipase A2 ActivitiesOnline Journal of Public Health Informatics, 2000
- Oxidized phospholipids activate PPARα in a phospholipase A2‐dependent mannerFEBS Letters, 2000