title: Regulation of the human hydroxysteroid sulfotransferase (SULT2A1) by RORα and RORγ and its potential relevance to human liver diseases.
abstract: The retinoid-related orphan receptors (RORs) were postulated to have functions in tissue development and circadian rhythm. In this study, we revealed a novel function of RORα (NR1F1) and RORγ (NR1F3) in regulating the human hydroxysteroid sulfotransferase (SULT2A1), a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. A combination of promoter reporter gene assay and EMSA and chromatin immunoprecipitation (ChIP) assays showed that both RORα and RORγ transactivated the SULT2A1 gene promoter through their binding to a ROR response element found in the SULT2A1 gene promoter. Interestingly, this ROR response element overlaps with a previously reported constitutive androstane receptor response element on the same promoter. Down-regulation of RORα and/or RORγ by small interfering RNA inhibited the expression of endogenous SULT2A1. In primary human hepatocytes and human livers, we found a positive correlation between the expression of SULT2A1 and RORs, which further supported the regulation of SULT2A1 by RORs. We also found that the expression of RORα and RORγ was impaired in several liver disease conditions, such as steatosis/steatohepatitis, fibrosis, and hepatocellular carcinoma. The positive regulation of human SULT2A1 by RORs is opposite to the negative regulation of Sult2a1 by RORs in rodents. In summary, our results established SULT2A1 as a novel ROR target gene. The expression of RORs is a potential predictor for the expression of SULT2A1 as well as disease conditions.
authors.affiliation: Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Ou
authors.forename: Xiongjie
authors.initials: X
authors.lastname: Shi
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gilroy
authors.forename: Levent
authors.initials: L
authors.lastname: Kirisci
authors.forename: Marjorie
authors.initials: M
authors.lastname: Romkes
authors.forename: Caitlin
authors.initials: C
authors.lastname: Lynch
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.forename: Mengxi
authors.initials: M
authors.lastname: Jiang
authors.forename: Songrong
authors.initials: S
authors.lastname: Ren
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D001483:Base Sequence; D000090702:Constitutive Androstane Receptor; D004790:Enzyme Induction; D005260:Female; D017930:Genes, Reporter; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020218:Response Elements; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000090702:Constitutive Androstane Receptor; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D008156:Luciferases; D015238:Sulfotransferases; C028152:alcohol sulfotransferase