Disease relevance of SLC10A2

• Analysis of the ileal bile acid transporter gene, SLC10A2, in subjects with familial hypertriglyceridemia [1].
• However, when study participants were subgrouped by body weight, ASBT and ILBP protein were 48% and 67% lower in normal weight gallstone carriers than in controls (P < 0.05); similar differences were found for mRNA expression levels [2].
• This initial observation of an association between a polymorphism in the SLC10A2 gene and the risk of colorectal adenomatous polyps would, if confirmed by other studies, support the role of bile acids in the carcinogenesis of colorectal cancer [3].
• Marked hypercholanemia and cholestasis are predicted to develop, presumably because of both enhanced ileal uptake of bile salts via up-regulation of the apical sodium-dependent bile acid transporter and diminished canalicular secretion of bile salts secondary to down-regulation of the bile salt excretory pump [4].
• Partial inhibition of ASBT may be useful in the treatment of hypercholesterolemia and intrahepatic cholestasis [5].

High impact information on SLC10A2

• RESULTS: In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after interleukin-1beta treatment, while c-fos and c-jun were up-regulated 2-fold [6].
• METHODS: Transient transfection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in cells treated with the inflammatory cytokines and/or various activator protein-1 constructs [6].
• METHODS: Interactions among the apical sodium-dependent bile acid transporter, the farnesoid X receptor (FXR), and familial intrahepatic cholestasis-1 were studied in the ileum of children with progressive familial intrahepatic cholestasis type 1 and in Caco-2 cells [4].
• RESULTS: Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with progressive familial intrahepatic cholestasis type 1 [4].
• Site-directed mutagenesis of an RAR/RXR cis element in the human ASBT promoter reduced its activity by 50% and eliminated the bile acid response [7].

Biological context of SLC10A2

• Membrane topology of human ASBT (SLC10A2) determined by dual label epitope insertion scanning mutagenesis. New evidence for seven transmembrane domains [8].
• Localization of the ileal sodium-bile acid cotransporter gene (SLC10A2) to human chromosome 13q33 [9].
• The SLC10A2 missense mutations and 5' flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects [1].
• NTCP and the ileal transporter ASBT (apical sodium-dependent bile acid transporter) are two sodium-dependent transporters critical for the enterohepatic circulation of bile acids [10].
• 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 [11].

Anatomical context of SLC10A2

• In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2 [1].
• To test this hypothesis, protein levels and mRNA expression of ASBT and ILBP were assessed in ileal mucosa biopsies of female gallstone carriers and controls [2].
• A deficiency of the apical sodium bile acid transporter (ASBT) and ileal lipid binding protein (ILBP) in the small intestine may result in bile acid loss into the colon and might promote gallstone formation by reducing the bile acid pool and increasing the amount of hydrophobic bile salts [2].
• In familial intrahepatic cholestasis-1-negative Caco-2 cells, the activity of the human apical sodium-dependent bile acid transporter promoter was enhanced, whereas the human FXR and bile salt excretory pump promoters' activities were reduced [4].
• Cell surface biotinylation and immunoblotting with epitope-specific and anti-hASBT antibodies confirmed expression and trafficking of the mutants to the plasma membrane [8].

Associations of SLC10A2 with chemical compounds

• Ciprofibrate treatment of SK-ChA cholangiocytes increased ASBT mRNA levels, suggesting a physiologic role for PPARalpha-mediated ASBT gene regulation [11].
• Transmembrane Domain VII of the Human Apical Sodium-Dependent Bile Acid Transporter ASBT (SLC10A2) Lines the Substrate Translocation Pathway [12].
• Retinoic acid activated the human ASBT promoter fourfold [7].
• CDCA treatment of Caco-2 cells led to a 75% reduction in steady-state ASBT messenger RNA levels and a 78% reduction in human ASBT promoter activity [7].
• In conclusion, 264W94 is a potent new cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model [13].

Physical interactions of SLC10A2

• Expression of the apical sodium-dependent bile acid transporter (ASBT) and of the organic anion transporting polypeptide (OATP-A) was detected and associated with sodium-dependent and sodium-independent [(3)H]taurocholate uptake in BEC [14].

Regulatory relationships of SLC10A2

• Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha [11].
• The hASBT gene is known to be activated by the glucocorticoid receptor (GR) [10].

Other interactions of SLC10A2

• CONCLUSIONS: Adult-onset IBAM is not directly related to dysfunctional mutations in the coding region or intron/exon junctions of the SLC10A2 gene [15].
• Neither ASBT nor ILBP levels differed significantly between gallstone carriers and controls [2].
• Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor [16].
• Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB [17].

Analytical, diagnostic and therapeutic context of SLC10A2

• Two distinct epitopes, hemagglutinin (HA) and FLAG, were individually inserted by inverted PCR mutagenesis at strategic positions along the hASBT sequence [8].
• Confocal microscopy confirmed membrane localization of epitope-tagged hASBT in saponin-treated (permeabilized) and nonpermeabilized transfected COS-1 and MDCK cells [8].
• The ASBT, FXR, and PPARalpha genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism (SSCP), denaturing HPLC, and direct sequencing [18].
• PATIENTS AND METHODS: ASBT expression in ileal biopsies from patients with Crohn's disease and from healthy subjects was quantified by western blot [16].
• ASBT promoter function was studied in luciferase assays and by electrophoretic mobility shift assay [16].

References