Hepatocellular and biliary epithelial transport proteins

Bilirubin glucuronides, reduced glutathione (GSH), and many other organic anions (except most bile salts) are actively transported across the bile canalicular membrane of hepatocytes by ABCC2 (also known as MRP2) against a concentration gradient. Bilirubin glucuronide transport is assisted by the –35mV intracellular potential maintained by Na+/K+ ATPase and the K+ channel on the sinusoidal and contiguous surfaces of the hepatocyte. The sinusoidal surface sodium-taurocholate cotransporting polypeptide, NTCP (encoded by SLC10A1), cotransports Na+ and bile salts from plasma into hepatocytes. The bile salt export protein BSEP (ABCB11) actively transports bile salts out of the hepatocyte into the bile canaliculus, stimulating bile flow. The canalicular surface multidrug resistance-3-P-glycoprotein MDR3 (ABCB4) mediates ATP-dependent translocation of phosphatidyl choline from the inner to the outer leaflet of the membrane bilayer, and from there to the bile, thereby protecting the canalicular membrane from the high concentration of bile salts actively transported into the bile. Canalicular ATP8B1 (FIC1) transports aminophospholipids from the outer to the inner leaflet of the membrane bilayer. A fraction of the bilirubin glucuronides is actively transported out of the sinusoidal surface membrane into the sinusoidal blood by ABCC3 (MRP3). Reuptake of the bilirubin glucuronides is by OATP1B1 and OATP1B3 (SLC01B1 and SLC01B3), which are located in the sinusoidal surface membrane of hepatocytes downstream of the sinusoidal blood flow.