In vivo role of aldehyde reductase

Motoko Takahashi, Satoshi Miyata, Junichi Fujii, Yoko Inai, Shigemitsu Ueyama, Motoko Araki, Tomoyoshi Soga, Reiko Fujinawa, Chiaki Nishitani, Shigeru Ariki, Takeyuki Shimizu, Tomomi Abe, Yoshito Ihara, Morimitsu Nishikimi, Yasunori Kozutsumi, Naoyuki Taniguchi, Yoshio Kuroki

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Aldehyde reductase (AKR1A; EC 1.1.1.2) catalyzes the reduction of various types of aldehydes. To ascertain the physiological role of AKR1A, we examined AKR1A knockout mice. Methods: Ascorbic acid concentrations in AKR1A knockout mice tissues were examined, and the effects of human AKR1A transgene were analyzed. We purified AKR1A and studied the activities of glucuronate reductase and glucuronolactone reductase, which are involved in ascorbic acid biosynthesis. Metabolomic analysis and DNA microarray analysis were performed for a comprehensive study of AKR1A knockout mice. Results: The levels of ascorbic acid in tissues of AKR1A knockout mice were significantly decreased which were completely restored by human AKR1A transgene. The activities of glucuronate reductase and glucuronolactone reductase, which are involved in ascorbic acid biosynthesis, were suppressed in AKR1A knockout mice. The accumulation of d-glucuronic acid and saccharate in knockout mice tissue and the expression of acute-phase proteins such as serum amyloid A2 are significantly increased in knockout mice liver. Conclusions: AKR1A plays a predominant role in the reduction of both d-glucuronic acid and d-glucurono-γ-lactone in vivo. The knockout of AKR1A in mice results in accumulation of d-glucuronic acid and saccharate as well as a deficiency of ascorbic acid, and also leads to upregulation of acute phase proteins. General significance: AKR1A is a major enzyme that catalyzes the reduction of d-glucuronic acid and d-glucurono-γ-lactone in vivo, besides acting as an aldehyde- detoxification enzyme. Suppression of AKR1A by inhibitors, which are used to prevent diabetic complications, may lead to the accumulation of d-glucuronic acid and saccharate.

Original languageEnglish
Pages (from-to)1787-1796
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1820
Issue number11
DOIs
Publication statusPublished - 2012 Nov

Keywords

  • Acute-phase protein
  • Glucose metabolism
  • Oxidoreductase
  • Transgenic rescue

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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    Takahashi, M., Miyata, S., Fujii, J., Inai, Y., Ueyama, S., Araki, M., Soga, T., Fujinawa, R., Nishitani, C., Ariki, S., Shimizu, T., Abe, T., Ihara, Y., Nishikimi, M., Kozutsumi, Y., Taniguchi, N., & Kuroki, Y. (2012). In vivo role of aldehyde reductase. Biochimica et Biophysica Acta - General Subjects, 1820(11), 1787-1796. https://doi.org/10.1016/j.bbagen.2012.07.003