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atRA upregulates SHP expression through RXR activation
Author(s) -
Won KyoungJae,
Jeong Hyunyoung
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.668.4
Subject(s) - retinoid x receptor , small heterodimer partner , retinoic acid , retinoid , downregulation and upregulation , nuclear receptor , cholesterol 7 alpha hydroxylase , retinoic acid receptor , chemistry , receptor , retinoid x receptor alpha , retinoid x receptor gamma , biology , transcription factor , cancer research , medicine , biochemistry , gene
Retinoids (vitamin A) are used therapeutically as an anticancer agent or to treat dermatological diseases. Common side effects of retinoid include hyperlipidemia. Previous studies have shown that all‐trans retinoic acid (atRA; the bioactive retinoid) upregulates small heterodimer partner (SHP; a transcriptional repressor) and downregulates CYP7A1 (the rate‐limiting enzyme converting cholesterol to a bile acid intermediate), potentially responsible for the side effects. However, the detailed molecular mechanisms remain unclear. In this study, we investigated the role of retinoic acid receptor (RAR; the cognate nuclear receptor for atRA) and its binding partner, retinoid X receptor (RXR), in the transcriptional regulation of SHP and CYP7A1. In primary human hepatocytes and HepaRG cells, atRA increased SHP mRNA level by 12.8‐ and 6.6‐fold, respectively, while dramatically decreasing CYP7A1 mRNA level. In these cells, atRA also increased the levels of SHP pre‐mRNA, suggesting transcriptional activation of SHP by atRA. mRNA half‐life of SHP (determined after actinomycin D treatment in HepaRG cells and human hepatocytes) was not altered by atRA. In HepaRG cells, treatment with an RAR isoform‐specific agonist (i.e., BMS753, CD2314, and BMS961 for RARα, RARβ and RARγ, respectively) caused minimal changes in SHP expression. On the other hand, treatment with an RXR agonist (SR11237) led to increased SHP expression to an extent comparable to that by atRA (3.9‐ and 4.3‐fold, respectively), suggesting that SHP upregulation by atRA is mediated by RXR rather than RAR. mRNA expression of target genes of other permissive nuclear receptors that partner with RXR (i.e., CYP3A4, CYP2B6, and BSEP) was also increased in the cells treated by the RXR agonist to an extent similar to that by atRA. SHP knockdown led to significant de‐repression of CYP7A1 expression in atRA‐treated human hepatocytes (by 80% at 3 h), suggesting a key role of SHP in downregulation of CYP7A1 by atRA. Taken together, results from this study suggest an important role of RXR (rather than RAR) in mediating atRA action on the regulation of hepatic SHP and CYP7A1 expression, as well as expression of other target genes of permissive nuclear receptors that partner with RXR. Support or Funding Information This study was supported by NIH (R01 GM112746).