Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor α

Abstract

The apical sodium-dependent bile salt transporter (ASBT/SLC10A2), also called the ileal bile acid transporter, mediates the intestinal absorption of bile salts. The efficiency of this transport process is a determinant of hepatic bile salt synthesis from cholesterol and of serum triglyceride levels. Our aim was to characterize the human ASBT gene promoter with respect to regulatory mechanisms that coordinately affect ASBT expression and hepatic lipid and bile salt metabolism. The minimal construct that confers full promoter activity contains three functional hepatocyte nuclear factor 1␣ (HNF1␣) recognition sites, explaining the dependence of ASBT gene expression upon HNF1␣. A nuclear receptor binding site arranged as a direct hexanucleotide repeat (DR1 motif) is localized ϳ1.6 kb upstream of the transcription initiation site. Constructs containing this element were transactivated by WY14643 and ciprofibrate, ligands of the peroxisome proliferator-activated receptor ␣ (PPAR␣), in Caco2 cells. The DR1 element was shown to bind the PPAR␣/9-cis-retinoic acid receptor heterodimer, and targeted mutagenesis of the DR1 motif abolished PPAR␣ responsiveness. Ciprofibrate treatment of SK-ChA cholangiocytes increased ASBT mRNA levels, suggesting a physiologic role for PPAR␣-mediated ASBT gene regulation. This study identifies PPAR␣ as a novel link between ileal bile salt absorption and hepatic lipid metabolism.

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

“…[11][12][13] In addition, Asbt was only induced by atorvastatin, which-analogous to human ASBT-could be related to PPAR-␣ stimulation. 45 Induced cholangiocellular Asbt could favor reabsorption of toxic bile acids from stagnant bile in (obstructed) bile ducts. Some of the effects of atorvastatin may also involve the SREBP-2 (sterol regulatory element-binding protein-2) system, as hypothesized for Mdr2.…”

The Role of Canalicular ABC Transporters in Cholestasis

“…Treatment with the PPARa agonist fenofibrate increased the canalicular expression of ABCB4 in human hepatoma cells, which may be beneficial in patients with inherited ABCB4 defects (i.e., PFIC3, LPAC, and ICP) (Ghonem et al, 2012). In addition, PPARa decreased bile acid synthesis (CYP7A1) and induced bile acid detoxification (SULT2A1, UGT2B4, UGT1A3) in animal models (Patel et al, 2000;Jung et al, 2002;Barbier et al, 2003;Fang et al, 2005). The PPAR agonist bezafibrate showed beneficial effects in PBC patients in pilot trials, although these results need to be confirmed by larger randomized-controlled clinical trials (Honda et al, 2013).…”

Intestinal bile acid physiology and pathophysiology

“…The mechanism is unclear, but it may be related to PPARα inhibition by BAs (possibly because of high blood levels), given that PPARα has been reported to transactivate ASBT transcription, as mentioned above [45,49] . Intestinal MRP2 but not MRP3 is decreased by cholestasis in rats [50] and in humans [48,51] , although the significance of these findings is uncertain.…”

“…IBABP is also regulated by PPARα/β in humans but not mice [43] , and can also be indirectly up-regulated by cholesterol through the activation of sterol-responsive element-binding protein 1c (SREBP1c) by LXR [44] . ASBT is also regulated by PPARα [45] . These changes are expected to increase BA uptake and possibly reduce cholesterol absorption, a putative mechanism of action of the hypolipemic drugs fibrates [43] .…”