title: Senescence marker protein-30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis.
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 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.
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Masutomi
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Handa
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Maruyama
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
keywords: AA, l-ascorbic acid; AST, aspartate aminotransferase; ApoB, Apolipoprotein B; Ascorbic acid; DHA, dehydroascorbic acid; DHE, dihydroethidium; DKO, double knockout; EDTA, ethylenediaminetetraacetic acid; FFA, free fatty acid; Grp78, glucose-regulated protein 78 kDa; KO, knockout; MTP, microsomal triglyceride transfer protein; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; Non-alcoholic fatty liver disease; PL, phospholipid; PPARα, peroxisome proliferator-activated receptor-α; Reactive oxygen species; SDS, sodium dodecyl sulfate; SMP30; SMP30, senescence marker protein-30; SOD, superoxide dismutase; SOD1; SREBP, sterol regulatory element binding protein; T-cho, total cholesterol; TBARS, thiobarbituric acid reactive substances; TG, triglyceride; VLDL, very low-density lipoprotein; qPCR, quantitative real-time polymerase chain reaction