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Tissue Specific Regulation of CYP26 Enzymes
Author(s) -
Tripathy Sasmita,
Isoherranen Nina
Publication year - 2017
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.31.1_supplement.669.10
Subject(s) - retinoic acid , biology , adipose tissue , cellular differentiation , microbiology and biotechnology , retinoic acid receptor , tretinoin , cell culture , endocrinology , biochemistry , gene , genetics
all‐trans ‐retinoic acid ( at RA) regulates many biological processes via RAR and PPAR mediated pathways. The metabolism and clearance of at RA is mediated by the CYP26A1 and CYP26B1 enzymes, that both appear to be critical retinoic acid hydroxylases during fetal development and adult life contributing to tissue specific regulation of at RA concentrations and signaling. CYP26A1 and CYP26B1 have different tissue specific expression both in adults and during development, and distinct switches occur between fetal expression patterns and adult tissues for both CYP26A1 and CYP26B1. In human fetal tissues CYP26A1 is exclusively expressed in brain, whereas CYP26B1 is not present in brain but found in other tissues. In adults, CYP26A1 is predominantly expressed in liver, whereas CYP26B1 is predominantly found in cerebellum and ubiquitously expressed in many other tissues such as adipose, testes, lymphocytes and kidney. While both CYP26A1 and CYP26B1 expression is believed to be regulated by at RA, the mechanisms that lead to distinct tissue specific expression and regulation of the CYP expression are not known. The aim of this study was to examine the tissue specific regulation of CYP26A1 and CYP26B1 by RAR and PPAR using various models of human liver, adipose and immune cells that reflect tissues specifically expressing CYP26A1 or CYP26B1. Our data revealed that constitutively CYP26A1 is predominantly expressed in liver cells, whereas CYP26B1 is found in adipocytes and lymphocytes. Similarly, CYP26A1 was highly inducible by at RA in liver cells while CYP26B1 was induced in adipocytes and lymphocytes. siRNA mediated knock down of nuclear receptors showed that CYP26A1 mRNA expression is solely regulated by RARα/β, whereas CYP26B1 expression is mainly regulated by PPARγ. These data suggest that the tissue specific expression of CYP26 enzymes is regulated by different nuclear receptors acting on the CYP26 promoter and that the two CYP26 enzymes will respond differently to endogenous and xenobiotic regulators of CYP expression. In conclusion, these findings may explain the different phenotypes observed after loss of CYP26A1 or CYP26B1 activity. Support or Funding Information Funding: NIH R01 GM111772