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The retinoic acid hydroxylase Cyp26a1 has minor effects on postnatal vitamin A homeostasis, but is required for exogenous atRA clearance

Year: 2019

Type: article

Abstract: The all- trans -retinoic acid ( at RA) hydroxylase Cyp26a1 is essential for embryonic development and may play a key role in regulating at RA clearance also in adults. We hypothesized that loss of Cyp26a1 activity via inducible knockout in juvenile or adult mice would result in decreased at RA clearance and increased tissue at RA concentrations and at RA-related adverse effects. To test these hypotheses, Cyp26a1 was knocked out in juvenile and adult male and female Cyp26a1 floxed mice using standard Cre–Lox technology and tamoxifen injections. Biochemical and histological methods were used to study the effects of global Cyp26a1 knockout. The Cyp26a1 knockout did not result in consistent histopathological changes in any major organs. Cyp26a1 −/− mice gained weight normally and exhibited no adverse phenotypes for up to 1 year after loss of Cyp26a1 expression. Similarly, at RA concentrations were not increased in the liver, testes, spleen, or serum of these mice, and the Cyp26a1 knockout did not cause compensatory induction of lecithin:retinol acetyltransferase ( Lrat ) or retinol dehydrogenase 11 ( Rdh11 ) mRNA or a decrease in aldehyde dehydrogenase 1a1 ( Aldh1a1 ) mRNA in the liver compared with tamoxifen-treated controls. However, the Cyp26a1 −/− mice showed increased bone marrow cellularity and decreased frequency of erythroid progenitor cells in the bone marrow consistent with a retinoid-induced myeloid skewing of hematopoiesis. In addition, the Cyp26a1 knockout decreased clearance of exogenous at RA by 70% and increased at RA half-life 6-fold. These findings demonstrate that despite lacking a major impact on endogenous at RA signaling, Cyp26a1 critically contributes as a barrier for exogenous at RA exposure.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.ra119.009023