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Review
. 2009 Dec;50(12):2340-57.
doi: 10.1194/jlr.R900012-JLR200. Epub 2009 Jun 4.

Bile acid transporters

Paul A Dawson  1 , Tian Lan, Anuradha Rao
Affiliations
Review

Bile acid transporters

Paul A Dawson et al. J Lipid Res. 2009 Dec.

Abstract

In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the Na(+) taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent fashion across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently indentified heteromeric organic solute transporter, OSTalpha-OSTbeta. In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles. This article will review our current understanding of the physiological role and regulation of these important carriers.

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Figures

Fig. 1.
Fig. 1.
Enterohepatic circulation of bile acids. Localization of the major transport proteins, NTCP, BSEP, ASBT, and OSTα-OSTβ of the enterohepatic circulation responsible for bile acid (BA) movement across hepatocytes, cholangiocytes, ileocytes (ileal enterocytes), and renal proximal tubule cells. In the liver, bile acids are efficiently extracted from portal blood by the Na+-taurocholate cotransporting polypeptide (NTCP; gene symbol SLC10A1) and resecreted across the canalicular membrane by the bile salt export pump (BSEP; gene symbol ABCB11). A fraction of the bile acids are absorbed by the epithelial cells lining the biliary tract (cholangiocytes) and sent back to the liver for resecretion into bile, a process termed cholehepatic shunting. The transcellular transport of bile acids across the biliary epithelium is mediated by the apical sodium bile acid transporter (ASBT, gene symbol SLC10A2) and the heteromeric transporter, OSTα-OSTβ, on the apical and basolateral membranes, respectively. Bile acids ultimately empty from the biliary tract into the small intestine where they are efficiently absorbed in the terminal ileum by the ASBT and OSTα-OSTβ and returned to the liver in the portal circulation. Bile acids that escape hepatic first-pass clearance are filtered by the kidney. Rather than be excreted in the urine, the bile acids are reabsorbed by the renal proximal tubule cells via the ASBT and OSTα-OSTβ and sent back to the liver for uptake and resecretion into bile. (Adapted with permission from Mosely RH: Bile secretion and cholestasis. In Kaplowitz N: Liver and Biliary Disease. 2nd ed. Philadelphia, Williams and Wilkins, 1996, p 194).
Fig. 2.
Fig. 2.
Model for differential regulation of hepatic bile acid synthesis. Bile acids are taken up by the ASBT and activate the nuclear receptor FXR to induce expression of OSTα-OSTβ and FGF15 in the ileal enterocyte. The bile acids are then released into the portal circulation via basolateral OSTα-OSTβ and reabsorbed by the hepatic sinusoidal (basolateral) transporter, NTCP. Bile acids are secreted across the apical (canalicular) membrane into the bile canaliculus via the BSEP and undergo another round of enterohepatic cycling. Ileal-derived FGF15 signals through its receptor, FGFR4, to repress Cyp7a1 expression and bile acid synthesis. A block in ileal brush border membrane uptake of bile acids results in downregulation of FXR target genes such as FGF15. The decreased FGF15 production and reduced return of bile acids to the liver leads to increased Cyp7a1 expression, increased hepatic conversion of cholesterol to bile acids, and reduced plasma cholesterol levels. This is the classical mechanism of action for the bile acid sequestrants. In contract, a block in ileal basolateral bile acid export leads to increased bile acid retention and increased FXR-mediated activation of FGF15 expression. Despite reduced return of bile acids in the enterohepatic circulation, the ileal-derived FGF15 signals to repress hepatic Cyp7a1 expression and bile acid synthesis. (From Davis and Attie (246); copyright 2008 National Academy of Sciences, USA).
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