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Biochim Biophys Acta. 2014 Jul;1840(7):2289-98. doi: 10.1016/j.bbagen.2014.03.019. Epub 2014 Apr 3.

Ascorbic acid deficiency affects genes for oxidation-reduction and lipid metabolism in livers from SMP30/GNL knockout mice.

Author information

1
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.
2
Faculty of Bioresource Sciences, Akita Prefectural University, Akita 010-0195, Japan.
3
Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
4
Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
5
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
6
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan. Electronic address: ishigami@tmig.or.jp.

Abstract

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.

GENERAL SIGNIFICANCE:

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.

KEYWORDS:

Ascorbic acid; Bile acid; Cyp7a1; Lipid metabolism; Microarray; Nrf2

PMID:
24704458
DOI:
10.1016/j.bbagen.2014.03.019
[Indexed for MEDLINE]

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