Impacts and mechanism of liver-specific knockout of selenoprotein I on hepatic phospholipid metabolism, selenogenome expression, redox status, and resistance to CCl toxicity.

Journal: Free radical biology & medicine
Published Date: May 7, 2025

Abstract

Selenoprotein I (SELENOI) was known initially as ethanolamine phosphotransferase 1 (EPT1) and later as a selenoprotein. Because global knockout of Selenoi in mice is embryonically lethal, we generated liver-specific Selenoi knockout (cKO) mice to reveal functions and mechanism of SELENOI in the liver. Compared with control mice, cKO mice (8 weeks old) had no differences in body weight, glucose metabolism, energy expenditure, overall health status, or liver histology. However, these mice had lower (P < 0.05) mRNA levels of 13 selenoprotein genes, contents of Se, GSH, and T-AOC (12-40%), and activities of antioxidant enzymes (17-51%), but higher (P < 0.05) mRNA levels of oxidative stress-related genes (34%-46%) in the liver than the control mice. They had a higher (P < 0.05) ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) due to increases of the former and decreases of the latter, altered PE and PC constituents such as n-6/n-3 PUFA ratios, and elevated mRNA levels (95%-2-fold, P < 0.05) of lipolysis genes, compared with the control mice. The knockout attenuated hepatic injury and fibrosis induced by 14 intraperitoneal injections of CCl (0.5 mL/kg). The protection was associated with adaptive cytoprotective mechanisms induced by the overall decline of redox status mediated by SELENOI as a selenoprotein and activations of PPAR signaling, fatty acid desaturase 2 (FADS2), glutathione S-transferase, and lipid peroxide hydrolysis through modulating biosynthesis and(or) constituents of PC, PE, and n-6/n-3 PUFAs mediated by SELENOI as EPT1. Inhibition of FADS2 in CCl-treated cKO hepatocytes partially removed the protection by the knockout. In conclusion, hepatic SELENOI expression was not essential for survival, but served as a multifunctional regulator of hepatic selenogenome expression, Se metabolism, redox status, biosyntheses and profiles of PC and PE, and resistance to CCI

Authors

  • Xu Zhang
    China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China.
  • Wei Xiong
    Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; Food Laboratory of Zhongyuan, Luohe, Henan 462300, China. Electronic address: xiongwei910702@126.com.
  • Fei Gao
    College of Biological Sciences, China Agricultural University, Beijing 100193, China.
  • Zhengquan Yu
    College of Biological Sciences, China Agricultural University, Beijing 100193, China; Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
  • Fazheng Ren
    Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
  • Xin Gen Lei
    Department of Animal Science, Cornell University, Ithaca, New York 14853, USA. Electronic address: XL20@cornell.edu.

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