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STa-OSTb (SLC51A and SLC51B) is a heteromeric Oorganic solute transporter that was first isolated from the liver of a marine skate, Leukoraja erinacia, by Ballatori’s lab in a quest for a sodium-independent transporter of hepatic bile acid uptake. Subsequent studies identified SLC51A and B orthologues from mice and humans. These 2 gene products are the only known members of this SLC family. The transporter is unique in requiring 2 subunits for function. Human SLC51A encodes for a 340–amino acid protein with 7 membrane-spanning domains whereas SLC51B encodes for a 128–amino acid single-membrane-spanning domain protein. Functional solute transport requires heterodimerization of both gene products for stability and delivery to the basolateral plasma membrane. OSTa-OSTb is expressed in many tissues, but primarily the distal intestine, renal proximal tubule, and bile duct, where it is known to transport bile acids across the basolateral membrane of the ileal enterocyte, renal proximal tubule, and the cholangiocyte. The mechanism of transport is by facilitated diffusion, either efflux or uptake, depending on the electrochemical gradient. OSTa-OSTb also transports steroids, particularly in the ovary, testes, and adrenal gland, as well as eicosanoids and possibly other sterols. Bile acid absorption from the intestinal lumen is performed by the apical sodium-dependent bile acid transporter (ASBT) in the ileal enterocyte. Bile acids then are transported by OSTa-OSTb across the basolateral membrane and out of the cell, back to the liver via the portal circulation. Together, ASBT and OSTa-OSTb are key regulators that maintain homeostasis of the bile acid pool and guard against tissue bile acid accumulation and toxicity via Farnesoid X Receptor (FXR)–fibroblast growth factor 15/19-fibroblast growth factor receptor 4 regulatory mechanisms. Deletion of Osta in mice produces a paradoxical phenotype compared with Asbt deletion: it reduces the bile acid pool size by approximately 50%, down-regulates rather than increases hepatic Cyp7A1 activity, decreases the absorption of intestinal lipids, and protects these animals from cholestatic injury induced by bile duct ligation or cholic acid feeding. Osta-/-mice also have an interesting intestinal phenotype manifested at birth by an increase in intestinal length, amarked decrease in villous heightwith accumulation of goblet cells on the apical mucosal surface, and an increase in epithelial proliferation. These observations raised the inevitable question as towhether these intestinal changes are the result of accumulation of toxic bile acids in the enterocyte. This is the subject of the article by Ferrebe et al in this month’s issue of Cellular and Molecular Gastroenterology and Hepatology. They focused on neonatal Osta-/mice and showed that the bile acid transporter, Asbt, is expressed

OSTα-OSTβ Guards the Ileal Enterocyte From the Accumulation of Toxic Levels of Bile Acids