The retinoic acid hydroxylase Cyp26a1 has minor effects on postnatal vitamin A homeostasis, but is required for exogenous atRA clearance release_wgcasu24o5hlzd33oyeau6teti

by Guo Zhong, Cathryn Hogarth, Jessica Snyder, Laura Palau, Traci Topping, Weize Huang, Lindsay Czuba, Jeffrey Lafrance, Gabriel Ghiaur, Nina Isoherranen

Published in Journal of Biological Chemistry by American Society for Biochemistry & Molecular Biology (ASBMB).

2019   Volume 294, Issue 29, jbc.RA119.009023

Abstract

The all-trans-retinoic acid (atRA) hydroxylase Cyp26a1 is essential for embryonic development and may play a key role in regulating atRA clearance also in adults. We hypothesized that loss of Cyp26a1 activity via inducible knockout in juvenile or adult mice would result in decreased atRA clearance and increased tissue atRA concentrations and atRA-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, atRA 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 atRA by 70% and increased atRA half-life 6-fold. These findings demonstrate that despite lacking a major impact on endogenous atRA signaling, Cyp26a1 critically contributes as a barrier for exogenous atRA exposure.
In text/plain format

Archived Files and Locations

application/pdf  4.0 MB
file_6ytohheoijcsjc6ak3mgc7gtee
web.archive.org (webarchive)
www.jbc.org (web)
Read Archived PDF
Archived
Type  article-journal
Stage   published
Date   2019-06-05
Language   en ?
Journal Metadata
Not in DOAJ
In Keepers Registery
ISSN-L:  0021-9258
Work Entity
access all versions, variants, and formats of this works (eg, pre-prints)
Catalog Record
Revision: 9beb753f-137c-4225-b332-8e6c22eb6739
API URL: JSON