Organic solute transporter, OSTalpha-OSTbeta: its role in bile acid transport and cholestasis

Abstract

Organic solute transporter alpha-beta (OSTalpha-OSTbeta) is a unique heteromeric transporter localized to the basolateral membrane of epithelial cells involved in sterol transport. It is believed to be the primary bile acid efflux transporter in the intestine of mammals and is therefore essential to bile acid homeostasis and the enterohepatic circulation. First described in the evolutionarily primitive small skate, LEUCORAJA ERINACEA, this facilitated transporter requires expression of both subunits for its function. It can transport a variety of bile acids, as well as estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, digoxin, and prostaglandin E (2). Expression of both subunits is variable between species and tissues; in humans high expression is noted in the liver, small intestine, kidney, testis, and adrenal gland. OSTalpha-OSTbeta is directly regulated by the bile acid sensing nuclear receptor, farnesoid X receptor (FXR). Furthermore, it is part of the complex regulatory pathway that controls bile acid synthesis and homeostasis. Hepatic OSTalpha-OSTbeta is upregulated in cholestasis in both humans and rodents, where it appears to play a protective role. Additional studies are necessary to determine its role in liver injury, bile acid malabsorption, and lipid and glucose metabolism, as well as a potential protective role for kidney OSTalpha-OSTbeta in cholestasis.

Figure 1

The nuclear receptor Car and Phase I and II enzymes are up-regulated in the liver after bile duct ligation in Ostα −/− mice. Quantitation RT-PCR results demonstrate that mRNA level for the nuclear receptor Car, but not Fxr or Pxr, is up-regulated after BDL in Ostα −/− mouse liver compared with wildtype BDL mice. mRNA for the Car target genes Cyp2b10, Cyp3a11, Sult2a1 and Ugt1a1 are also up-regulated compared with the wildtype BDL liver. Down-regulation of the repressor Shp and up-regulation of Cyp7a1 may result in an increase in the bile acid pool in these cholestatic mice. n = 4–6/group; *p<0.05

Figure 2

Adaptive regulation of key transporters in the kidney of Ostα −/− mice provide protection from obstructive cholestasis. The increased serum bile acids in BDL mice cannot be efficiently reabsorbed in the kidney because of the decreased expression of apical Asbt and the absence of basolateral Ostα-Ostβ. Furthermore, an up-regulation of the apical export transporters, Mrp2 and Mrp4, efficiently prevents further retention of bile acids in the kidney. Therefore, ~3 fold more bile acids are excreted into the urine and removed from the body after BDL, compared with wild type mice.