Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha.
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 1alpha (HNF1alpha) recognition sites, explaining the dependence of ASBT gene expression upon HNF1alpha. A nuclear receptor binding site arranged as a direct hexanucleotide repeat (DR1 motif) is localized approximately 1.6 kb upstream of the transcription initiation site. Constructs containing this element were transactivated by WY14643 and ciprofibrate, ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha), in Caco2 cells. The DR1 element was shown to bind the PPARalpha/9-cis-retinoic acid receptor heterodimer, and targeted mutagenesis of the DR1 motif abolished PPARalpha responsiveness. Ciprofibrate treatment of SK-ChA cholangiocytes increased ASBT mRNA levels, suggesting a physiologic role for PPARalpha-mediated ASBT gene regulation. This study identifies PPARalpha as a novel link between ileal bile salt absorption and hepatic lipid metabolism.
Jung
Diana
D
Laboratory of Molecular Gastroenterology and Hepatology, Division of Clinical Pharmacology and Toxicology, University Hospital, CH-8091 Zurich, Switzerland.
Fried
Michael
M
Kullak-Ublick
Gerd A
GA
D020121:5' Untranslated Regions; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism; D001665:Binding Sites; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins; D019281:Dimerization; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D009687:Nuclear Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors; D027981:Symporters; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D020121:5' Untranslated Regions; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D027981:Symporters; D015534:Trans-Activators; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; C071908:sodium-bile acid cotransporter