Ascorbic acid deficiency affects genes for oxidation-reduction and lipid metabolism in livers from SMP30/GNL knockout mice.
BACKGROUND
We sought to elucidate the effect of an ascorbic acid (AA) deficiency on gene expression, because the water soluble antioxidant AA is an important bioactive substance in vivo.


METHODS
We performed microarray analyses of the transcriptome in the liver from senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which are unable to synthesize AA in vivo.


RESULTS
Our microarray analysis revealed that the AA deficiency increased gene expression related to the oxidation-reduction process, i.e., the nuclear factor, erythroid derived 2, like 2 (Nrf2) gene, which is a reactive oxygen species-sensitive transcriptional factor. Moreover, this AA deficiency increased the expression of genes for lipid metabolism including the cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1), which is a late-limiting enzyme of the primary bile acid biosynthesis pathway. Although an AA deficiency increased the Cyp7a1 protein level, bile acid levels in the liver and gallbladder decreased. Since Cyp7a1 has a heme iron at the active site, AA must function as a reductant of the iron required for the continuous activation of Cyp7a1.


CONCLUSIONS
This experimental evidence strongly supports a role for AA in the physiologic oxidation-reduction process and lipid metabolism including bile acid biosynthesis.


CONCLUSIONS
Although many effects of AA supplementation have been reported, no microarray analysis of AA deficiency in vivo is available. Results from using this unique model of AA deficiency, the SMP30/GNL-KO mouse, now provide new information about formerly unknown AA functions that will implement further study of AA in vivo.
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Keita
K
Takahashi
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Yuki
Y
Kishimoto
Faculty of Bioresource Sciences, Akita Prefectural University, Akita 010-0195, Japan.
Tomokazu
T
Konishi
Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Yasunori
Y
Fujita
Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Masafumi
M
Ito
Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Kentaro
K
Shimokado
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Naoki
N
Maruyama
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan. Electronic address: ishigami@tmig.or.jp.
Akihito
A
Ishigami
D000818:Animals; D001205:Ascorbic Acid / Q000096:biosynthesis / Q000378:metabolism*; D001206:Ascorbic Acid Deficiency / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D010084:Oxidation-Reduction; D059467:Transcriptome
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C513324:Rgn protein, mouse; D001205:Ascorbic Acid
Ascorbic acid; Bile acid; Cyp7a1; Lipid metabolism; Microarray; Nrf2