The SLCO1A2 Gene, Encoding Human Organic Anion-Transporting Polypeptide 1A2, Is Transactivated by the Vitamin D Receptor

Abstract

Organic anion-transporting polypeptide 1A2 (OATP1A2) (gene symbol, SLCO1A2) mediates cellular uptake of a wide range of endogenous substrates, as well as drugs and xenobiotics. OATP1A2 is expressed in several tissues, including apical membranes of small intestinal epithelial cells. Given its role in intestinal drug absorption, a detailed analysis of the mechanisms that regulate SLCO1A2 gene expression is potentially of great pharmacological relevance. We show here that treatment of human intestine-derived Caco-2 cells with vitamin D 3 markedly increased endogenous OATP1A2 mRNA and protein levels. Suppression of endogenous vitamin D receptor (VDR) expression with siRNAs significantly reduced this induction. Two alternative promoter regions exist in genomic databases for the SLCO1A2 gene. One putative VDR response element (VDRE) that was predicted to interact efficiently with VDR-retinoid X receptor ␣ (RXR␣) was identified in silico within SLCO1A2 promoter variant 1. This VDRE served as a strong binding site for the recombinant VDR-RXR␣ heterodimers in vitro and was potently activated by VDR in the presence of vitamin D 3 in heterologous promoter assays. In reporter assays using native promoter constructs, SLCO1A2 promoter variant 1 was strongly induced by VDR, and site-directed mutagenesis of a single VDRE within this region abolished this activation. Native VDR-RXR␣ also interacted with this element both in vitro and in living cells. We showed that expression of the SLCO1A2 gene is induced by vitamin D 3 at the transcriptional level through the VDR. Our results suggest that pharmacological administration of vitamin D 3 may allow modulation of intestinal absorption of OATP1A2 transport substrates.

Nuclear-receptor–mediated regulation of drug– and bile-acid–transporter proteins in gut and liver

“…These studies show a significant increase in the expression of OATP1A2 messenger RNA (mRNA) after 24-hour treatment with 500 nM of vitamin D 3 as well as after treatment of 50 μM of lithocholic acid (LCA), a VDR agonist, which was attenuated after small interfering RNA (siRNA)-mediated knockdown of VDR. This study also demonstrated an increase in OATP1A2 protein levels after 8 hours of treatment with vitamin D 3 (Eloranta et al, 2012). Taken together, these data strongly implicate VDR in the regulation of OATP1A2 in a manner that parallels PXR-mediated regulation in human model systems.…”

The Active Form of Vitamin D Transcriptionally Represses Smad7 Signaling and Activates Extracellular Signal-regulated Kinase (ERK) to Inhibit the Differentiation of a Inflammatory T Helper Cell Subset and Suppress Experimental Autoimmune Encephalomyelitis

“…We found a putative VDRE at position Ϫ1031 to Ϫ1046 from the transcription start site on the minus strand of Smad7 promoter; however, we could not identify any VDRE on the Smad3 promoter ( Fig. 2A) (33,34). The VDRE on Smad7 was the DR3 type with one consensus and one non-consensus half-site.…”

Organic Anion-Transporting Polypeptides

“…(Godoy, et al, 2013; Hagenbuch & Stieger, 2013; Klaassen & Aleksunes, 2010). Lately, the vitamin D receptor VDR has been added to this list, and it has been shown to activate the expression of SLCO1A2 (Eloranta, Hiller, Juttner, & Kullak-Ublick, 2012). As ligands for nuclear receptors are also substrates for OATPs (Gui, et al, 2008), the transporters may, to some extent, control the access of nuclear receptor ligands to their own genes.…”