Comparative Effects of Glutathione Peroxidase‐1 Overexpression and Cu/Zn‐superoxide Dismutase Knockout on Murine Hepatic Fatty Acid Metabolism

Abstract

Glutathione peroxidase‐1 (GPX1) and Cu/Zn‐superoxide dismutase (SOD1) are two major antioxidant enzymes, while polyunsaturated fatty acids (PUFA) including eicosapentaenoic acid (20:5n‐3, EPA) and docosahexaenoic acid (22:6n‐3, DHA) are health‐promoting nutrients. This study was conducted to determine the effects of GPX1 overexpression and SOD1 knockout on hepatic synthesis, accumulation, and oxidation of PUFA. GPX1 overexpressing (OE, 6–7 mo), and SOD1 knockout (SKO, 2 mo) mice and their respective wild‐type controls were fed a Torula yeast basal diet supplemented with 0 or 5% defatted microalgae (Nannochloropsis oceanica, 16% EPA) for 8 wk (n = 5 to 7 per group). Overexpression of GPX1 decreased (P < 0.01) linoleic acid (18:2n‐6) concentration and raised (P < 0.05) ω‐3/ω‐6 fatty acid ratio in the liver of mice regardless of diets. In comparison, knockout of SOD1 decreased (P < 0.05) concentrations of PUFA, in particular eicosatrienoic acid (20:3n‐3, precursor of EPA) and DHA, in mice fed both diets. The knockout of SOD1 also resulted in lower (P < 0.01) hepatic ω‐3/ω‐6 fatty acid ratio than the wild‐type mice when both genotypes were fed the algae diet. Inclusion of 5% algae in the diet elevated (P < 0.05) the hepatic DHA concentration in only wild‐type mice of SOD1. Results of qPCR analysis showed that knockout of SOD1 down‐regulated (P < 0.05) hepatic mRNA levels of elongase 2 and 5, the major enzymes involved in long chain PUFA synthesis, compared with the wild‐type controls. Meanwhile, the OE mice had lower (P < 0.05) hepatic mRNA levels of PUFA oxidation‐related genes including cyclooxygenase 1 (COX1), COX2, and arachidonate 5‐lipoxygenase than their wild‐type controls. In addition, feeding the algae diet decreased (P < 0.01) non‐esterified fatty acid concentrations in both plasma and liver of the OE mice, and concentration of triglycerides in the liver of the SOD1 wild‐type mice. In conclusion, overexpression of GPX1 and knockout of SOD1 exerted differential effects on synthesis, accumulation and oxidation of hepatic PUFA in mice. Further study requires to measure oxidized metabolites of PUFA and to reveal molecular mechanisms by which GPX1 and SOD1 regulate PUFA metabolism.Support or Funding InformationSupported in part by a NIH grant DK53018 and a USDA/DOE Biomass R&D Initiative Grant