Open AccessSenescence marker protein‐30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis
Author(s) -
Kondo Yoshitaka,
Masutomi Hirofumi,
Noda Yoshihiro,
Ozawa Yusuke,
Takahashi Keita,
Handa Setsuko,
Maruyama Naoki,
Shimizu Takahiko,
Ishigami Akihito
Publication year - 2014
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1016/j.fob.2014.05.003
Subject(s) - medicine , endocrinology , oxidative stress , chemistry , superoxide dismutase , superoxide , sod1 , tbars , antioxidant , lipid peroxidation , biochemistry , biology , enzyme
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 Ca 2+ efflux by activating the calmodulin‐dependent Ca 2+ ‐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 14 days 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 89 days of age, respectively. Compared to wild type, SMP30‐KO and SOD1‐KO mice, by 14 days 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.