SLC10A2 Membrane Protein Introduction

Introduction of SLC10A2

SLC10A2 is a gene that in humans encodes the bile acid: a sodium symporter known as the apical sodium–bile acid transporter (ASBT) or as the ileal bile acid transporter (IBAT). It is highly expressed in the ileum, where it is found on the brush border membrane of enterocytes. It takes the responsibility to mediate the initial uptake of particularly conjugated bile acids, from the intestine as part of their enterohepatic circulation. Several medications to inhibit IBAT are under development. They include elobixibat, one situation under development for the treatment of constipation and irritable bowel syndrome, and volixibat, another situation under development for the treatment of nonalcoholic steatohepatitis.

Function of SLC10A2 Membrane Protein

SLC10A2 plays a vital role in the sodium-dependent reabsorption of bile acids from the lumen in the small intestine and in cholesterol metabolism. It also takes part in bile acid:sodium symporter activity and bile acid and bile salt transport. As a member of the bile acid-Na(+) symporter (bass) family, it plays a role in recycling of bile acids and salts in vivo.

Fig.1 Proposed mechanisms for enterobacteria-mediated regulation of hepatobiliary bile acid levels. (Miyata, 2011)

Application of SLC10A2 Membrane Protein in Literature

1. Lionarons D.A. Evolution of substrate specificity for the bile salt transporter ASBT (SLC10A2). J Lipid Res. 2012, 53(8):1535-42. PubMed ID: 22669917
   
   

   This article shows that human ASBT demonstrates high affinity for all three bile salt types. These findings suggest that ASBT changes from the earliest vertebrates by gaining affinity for modern bile salts while retaining affinity for older bile salts. This indicates that the bile salt enterohepatic circulation is conserved throughout vertebrate evolution at the same time.

2. Lundåsen T., et al. Inhibition of intestinal bile acid transporter Slc10a2 improves triglyceride metabolism and normalizes elevated plasma glucose levels in mice. PLoS One. 2012, 7(5):e37787. PubMed ID: 22662222
   
   

   This article shows that inhibition of Slc10a2 in diabetic ob/ob mice can reduce serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c. Moreover, those of Mek1/2-Erk1/2 and Akt are restrained after treatment of ob/ob mice with the Slc10a2 inhibitor.

3. Khantwal C.M., et al. Cytosolic half of transmembrane domain IV of the human bile acid transporter hASBT (SLC10A2) forms part of the substrate translocation pathway. Biochemistry. 2008, 47(12):3606-14. PubMed ID: 18311924
   
   

   The authors report the involvement of transmembrane domain 4 (TM4) of hASBT in forming the putative translocation pathway. Their results demonstrate that primarily the cytosolic half of TM4 is highly solvent-accessible and plays an important role in ASBT function and substrate translocation. Consistent with the existing experimental data, a three-dimensional model for the orientation of TM4 is proposed.

4. Ho R.H., et al. Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). J Gastroenterol Hepatol. 2011, 26(12):1740-8. PubMed ID: 21649730
   
   

   The study reveals two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport. Examination of ASBT protein expression reveals no significant differences in expression or trafficking to the cell surface among variants versus wild-type ASBT. Analysis of ASBT mRNA and protein expression in human intestinal samples reveals modest intersubject variability. It reveals the presence of multiple functionally relevant variants in SLC10A2 that may influence bile acid homeostasis and physiology.

5. Tönjes A., et al. Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts. BMC Med Genet. 2011, 12:149. PubMed ID: 22093174
   
   

   This article suggests that there is no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p> 0.05). There is an effect trend in the subgroup of lean subjects while it is based on different effect directions in the three cohorts there is no significant association in the meta-analysis.

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Reference

1. Miyata M, et al. (2011). Enterobacteria modulate intestinal bile acid transport and homeostasis through apical sodium-dependent bile acid transporter (SLC10A2) expression. Journal of Pharmacology & Experimental Therapeutics. 336(1), 188.

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