Preclinical/Animal Transporters

Asbt - rat

Asbt (apical sodium-dependent bile acid transporter), rat


Aliases: IBAT, ISBAT, ISBT
Gene name: Solute carrier family 10 member 2 (Slc10a2)

The rat ileal sodium-dependent bile acid (BA) cotransporter was cloned and expressed in Xenopus oocytes in 1995 [1]. The human and rat orthologs share 83% amino acid homology. Expression of rAsbt has been detected on the apical surface of ileal enterocytes, renal proximal tubular cells and cholangiocytes, similar to the human protein [2-4]. An alternatively spliced variant named t-Asbt is localized to the basolateral domain of cholangiocytes, ileal enterocytes, and renal tubular epithelial cells. This truncated variant exhibited activity as a taurocholic acid efflux carrier in in vitro experiments in Xenopus oocytes [5]. Regulation of both variants by BAs was investigated by several groups, but no consensus was achieved as to whether a negative feedback regulatory mechanism similar to mice and humans exists [6-9].
Studying the effect of Asbt/ASBT inhibitors in animal models for BA-related diseases can help to find novel approaches for disease control. In Zucker diabetic obese rats, oral administration of an Asbt inhibitor significantly decreased glucose levels and prevented the drop of insulin levels in a dose-dependent manner [10]. In the Zucker rat model of obesity, Asbt activity was significantly increased in intact ileal villus cells compared to cells from wild type rat. Western blot studies suggested that the increase in transporter activity was a consequence of increased expression of the Asbt protein [11].
Enhancing intestinal absorption through BA-derived prodrugs that target Asbt/ASBT is a relatively new strategy. A cholyl-insulin formulation was shown to be absorbed from rat small intestine, and the absorption was specific to the ileum and could be blocked by taurocholate [12]. By orally administering deoxycholic acid-modified chitosan nanoparticles loaded with insulin, a bioavailability of 16% was achieved in type I diabetic rats. Intravital two-photon microscopy revealed that the transport of the nanoparticles into the intestinal villi was mediated by Asbt [13].


References


1.    Shneider, B.L., et al., Cloning and molecular characterization of the ontogeny of a rat ileal sodium-dependent bile acid transporter. J Clin Invest, 1995. 95(2): p. 745-54.
2.    Lazaridis, K.N., et al., Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest, 1997. 100(11): p. 2714-21.
3.    Christie, D.M., et al., Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum. Am J Physiol, 1996. 271(2 Pt 1): p. G377-85.
4.    Kullak-Ublick, G.A., B. Stieger, and P.J. Meier, Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology, 2004. 126(1): p. 322-42.
5.    Lazaridis, K.N., et al., Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proc Natl Acad Sci U S A, 2000. 97(20): p. 11092-7.
6.    Kip, N.S., et al., Differential expression of cholangiocyte and ileal bile acid transporters following bile acid supplementation and depletion. World J Gastroenterol, 2004. 10(10): p. 1440-6.
7.    Chen, F., et al., Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter. J Biol Chem, 2003. 278(22): p. 19909-16.
8.    Arrese, M., et al., Neither intestinal sequestration of bile acids nor common bile duct ligation modulate the expression and function of the rat ileal bile acid transporter. Hepatology, 1998. 28(4): p. 1081-7.
9.    Shneider, B.L., Intestinal bile acid transport: biology, physiology, and pathophysiology. J Pediatr Gastroenterol Nutr, 2001. 32(4): p. 407-17.
10.    Chen, L., et al., Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes. Am J Physiol Endocrinol Metab, 2012. 302(1): p. E68-76.
11.    Sundaram, S., et al., Mechanism of Dyslipidemia in Obesity-Unique Regulation of Ileal Villus Cell Brush Border Membrane Sodium-Bile Acid Cotransport. Cells, 2019. 8(10).
12.    McGinn, B.J. and J.D. Morrison, Investigations into the absorption of insulin and insulin derivatives from the small intestine of the anaesthetised rat. J Control Release, 2016. 232: p. 120-30.
13.    Fan, W., et al., Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials, 2018. 151: p. 13-23.

 

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