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CYP26A1 mRNA downregulation compensates for targeted disruption of retinol dehydrogenase 1 (Rdh1)
Author(s) -
Zhang Min,
Hu Peirong,
Napoli Joseph L
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a99-d
Subject(s) - retinol , retinoic acid , vitamin , biology , retinol binding protein , vitamin a deficiency , biochemistry , medicine , endocrinology , gene
Retinoic acid (RA), an activated metabolite of vitamin A (all‐ trans ‐retinol), controls multiple pathways essential for vertebrate embryonic development and perinatal growth and function. Rdh1 is the most efficient enzyme known (Vm/K m ) that catalyzes dehydrogenation of all‐ trans ‐retinol, contributes to a reconstituted path of atRA biosynthesis in intact cells, and belongs to a family of enzymes (short‐chain dehydrogenases/reductases, SDR) capable of recognizing the physiological form of vitamin A, retinol bound with cellular retinol binding‐protein. To further assess the function of Rdh1 in RA homeostasis, the murine gene was disrupted by homologous recombination. Null mice fed a retinol‐enriched diet were born in Mendalian ratio, and remained healthy and fertile. They did not present with any of the morphological abnormalities of vitamin A deficiency. The Rdh1 null mouse, however, had a 2‐fold greater all‐ trans ‐retinol in liver than wild‐type. Interestingly, the mRNA of Cyp26A1, a major catalyst of RA degradation, was down‐regulated 3‐fold in livers of Rdh1 null mice fed a diet with standard or marginal amounts of vitamin A. Thus, the vitamin A normal phenotype was achieved through compensation by decreased expression of the major atRA degrading enzyme in the liver. Consistent with this function for CYP26A1, mRNA expression levels of CYP26A1 and Rdh1 showed a strong inverse relationship in the whole embryo from e7.5 to e18.5 and in the liver from e12.5 to P2M. This is the first genetic evidence for a function of a specific retinol dehydrogenase in a phyisological pathway of atRA generation. This work was supported by NIH grant DK36870.