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.