Keita Takahashi1, Yuki Kishimoto1, Tomokazu Konishi2, Yasunori Fujita3, Masafumi Ito3, Kentaro Shimokado4, Naoki Maruyama5, Akihito Ishigami6. 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.
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 hemeiron 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.
Authors: Young-Sook Son; H M Arif Ullah; Ahmed K Elfadl; Myung-Jin Chung; Soong-Gu Ghim; Yong Deuk Kim; Eun-Joo Lee; Kyung-Ku Kang; Kyu-Shik Jeong Journal: In Vivo Date: 2018 Jan-Feb Impact factor: 2.155
Authors: Emma Watson; Viridiana Olin-Sandoval; Michael J Hoy; Chi-Hua Li; Timo Louisse; Victoria Yao; Akihiro Mori; Amy D Holdorf; Olga G Troyanskaya; Markus Ralser; Albertha Jm Walhout Journal: Elife Date: 2016-07-06 Impact factor: 8.140
Authors: Yulia Shulpekova; Elena Shirokova; Maria Zharkova; Pyotr Tkachenko; Igor Tikhonov; Alexander Stepanov; Alexandra Sinitsyna; Alexander Izotov; Tatyana Butkova; Nadezhda Shulpekova; Vladimir Nechaev; Igor Damulin; Alexey Okhlobystin; Vladimir Ivashkin Journal: Molecules Date: 2022-03-18 Impact factor: 4.411