Transcriptional Regulation of Human Hydroxysteroid Sulfotransferase SULT2A1 by LXRα

Abstract

The nuclear receptor liver X receptor (LXR) plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. In this study, we uncovered a function of LXRa (NR1H3) in regulating the human hydroxysteroid sulfotransferase SULT2A1, a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. We showed that activation of LXR induced the expression of SULT2A1 at mRNA, protein, and enzymatic levels. A combination of promoter reporter gene and chromatin immunoprecipitation assays showed that LXRa transactivated the SULT2A1 gene promoter through its specific binding to the 2500-to 2258-base pair region of the SULT2A1 gene promoter. LXR small interfering RNA knockdown experiments suggested that LXRa, but not LXRb, played a dominant role in regulating SULT2A1. In primary human hepatocytes, we found a positive correlation between the expression of SULT2A1 and LXRa, which further supported the regulation of SULT2A1 by LXRa. In summary, our results established human SULT2A1 as a novel LXRa target gene. The expression of LXRa is a potential predictor for the expression of SULT2A1 in human liver.

Uncovering Drug-Responsive Regulatory Elements

“…Mutation of this putative DR4 in the context of the 500 bp promoter abolished the transactivation by LXRα. A positive correlation between the expression of SULT2A1 and LXRα was shown in primary human hepatocytes, which further supported the regulation of SULT2A1 by LXRα and establishes human SULT2A1 as a novel LXRα target gene [43]. …”

“…The expression of SULT2A1 is transcriptionally regulated by several nuclear receptors, including the liver X receptor (LXR) α (also called NR1H3). LXRα was shown to bind to the SULT2A1 promoter region [43]. The activation of LXRα by GW3965, a liver X receptor agonist (activator) of human LXRα, induced the expression of SULT2A1 at mRNA, protein and enzymatic levels.…”

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

“…VDR and PXR are activated by lithocholate and regulate the transcription of SULT2A1 (Makishima et al, 2002;Echchgadda et al, 2004;Fang et al, 2007). Additionally, LXR regulates the expression of SULT2A1 and 2B1b (Jiang et al, 2005;Ou et al, 2014), and several oxysterols that are ligands for LXR are also sulfonated by these enzymes (Fuda et al, 2007;Cook et al, 2009). Although cholecalciferol, produced from 7DHC in the skin, was not an efficient substrate (Xiangrong et al, 2000), desmosterol, 7DHC, and other postsqualene metabolites can be sulfonated (Masse et al, 1982;Axelson, 1987;Hu et al, 2015).…”

Identification and Evaluation of Biomarkers for Niemann-Pick Disease Type C Based on Chemical Analysis Techniques

“…However, cholenoic acid and its conjugates are superior in terms of analysis simplicity (no derivatization requirements) and sensitivity of LC/MS/MS analysis. From a biological perspective, oxysterols also exhibit various physiological actions via the liver X nuclear receptor [86][87][88], but its relationship with the pathophysiological mechanism in NPC remains largely unknown. Sulfate conjugations of bile acids are generally considered to be part of a detoxification system for accumulated cholesterol [89].…”