Bile acid transporters: structure, function, regulation and pathophysiological implications.
Specific transporters expressed in the liver and the intestine, play a critical role in driving the enterohepatic circulation of bile acids. By preserving a circulating pool of bile acids, an important factor influencing bile flow, these transporters are involved in maintaining bile acid and cholesterol homeostasis. Enterohepatic circulation of bile acids is fundamentally composed of two major processes: secretion from the liver and absorption from the intestine. In the hepatocytes, the vectorial transport of bile acids from blood to bile is ensured by Na+ taurocholate co-transporting peptide (NTCP) and organic anion transport polypeptides (OATPs). After binding to a cytosolic bile acid binding protein, bile acids are secreted into the canaliculus via ATP-dependent bile salt excretory pump (BSEP) and multi drug resistant proteins (MRPs). Bile acids are then delivered to the intestinal lumen through bile ducts where they emulsify dietary lipids and cholesterol to facilitate their absorption. Intestinal epithelial cells reabsorb the majority of the secreted bile acids through the apical sodium dependent bile acid transporter (ASBT) and sodium independent organic anion transporting peptide (OATPs). Cytosolic ileal bile acid binding protein (IBABP) mediates the transcellular movement of bile acids to the basolateral membrane across which they exit the cells via organic solute transporters (OST). An essential role of bile acid transporters is evident from the pathology associated with their genetic disruption or dysregulation of their function. Malfunctioning of hepatic and intestinal bile acid transporters is implicated in the pathophysiology of cholestatic liver disease and the depletion of circulating pool of bile acids, respectively. Extensive efforts have been recently made to enhance our understanding of the structure, function and regulation of the bile acid transporters and exploring new potential therapeutics to treat bile acid or cholesterol related diseases. This review will highlight current knowledge about structure, function and molecular characterization of bile acid transporters and discuss the implications of their defects in various hepatic and intestinal disorders.
Alrefai
Waddah A
WA
Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA. walrefai@uic.edu
Gill
Ravinder K
RK
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D016764:Cell Polarity; D002779:Cholestasis / Q000378:metabolism* / Q000503:physiopathology; D020895:Enterocytes / Q000378:metabolism; D004764:Enterohepatic Circulation; D004847:Epithelial Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D011487:Protein Conformation; D027981:Symporters / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D027981:Symporters; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter