Senescence marker protein-30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis

Yoshitaka Kondo, Hirofumi Masutomi, Yoshihiro Noda, Yusuke Ozawa, Keita Takahashi, Setsuko Handa, Naoki Maruyama, Takahiko Shimizu, Akihito Ishigami

Research output: Contribution to journalArticle

Abstract

Superoxide dismutase 1 (SOD1) is an antioxidant enzyme that converts superoxide anion radicals into hydrogen peroxide and molecular oxygen. The senescence marker protein-30 (SMP30) is a gluconolactonase that functions as an antioxidant protein in mammals due to its involvement in ascorbic acid (AA) biosynthesis. SMP30 also participates in Ca2+ efflux by activating the calmodulin-dependent Ca2+-pump. To reveal the role of oxidative stress in lipid metabolism defects occurring in non-alcoholic fatty liver disease pathogenesis, we generated SMP30/SOD1-double knockout (SMP30/SOD1-DKO) mice and investigated their survival curves, plasma and hepatic lipid profiles, amounts of hepatic oxidative stress, and hepatic protein levels expressed by genes related to lipid metabolism. While SMP30/SOD1-DKO pups had no growth retardation by 14days of age, they did have low plasma and hepatic AA levels. Thereafter, 39% and 53% of male and female pups died by 15-24 and 89days of age, respectively. Compared to wild type, SMP30-KO and SOD1-KO mice, by 14days SMP30/SOD1-DKO mice exhibited: (1) higher plasma levels of triglyceride and aspartate aminotransferase; (2) severe accumulation of hepatic triglyceride and total cholesterol; (3) higher levels of superoxide anion radicals and thiobarbituric acid reactive substances in livers; and (4) decreased mRNA and protein levels of Apolipoprotein B (ApoB) in livers - ApoB is an essential component of VLDL secretion. These results suggest that high levels of oxidative stress due to concomitant deficiency of SMP30 and/or AA, and SOD1 cause abnormal plasma lipid metabolism, hepatic lipid accumulation and premature death resulting from impaired VLDL secretion.

Original languageEnglish
Pages (from-to)522-532
Number of pages11
JournalFEBS Open Bio
Volume4
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Ascorbic acid
  • Non-alcoholic fatty liver disease
  • Reactive oxygen species
  • SMP30
  • SOD1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Kondo, Y., Masutomi, H., Noda, Y., Ozawa, Y., Takahashi, K., Handa, S., Maruyama, N., Shimizu, T., & Ishigami, A. (2014). Senescence marker protein-30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis. FEBS Open Bio, 4, 522-532. https://doi.org/10.1016/j.fob.2014.05.003