Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance.
Bilirubin is taken up from blood into hepatocytes by sinosuidal membrane transporters and then excreted into bile through the bile canalicular membrane mainly as bilirubin glucuronides. (1) Mechanism of bilirubin uptake into hepatocytes: many organic anions are incorporated into hepatocytes by organic anion transporting polypeptides (rat, oatp1, oatp2, oatp3; human, OATP), liver-specific transporter (rlst/HLST), and/or by organic anion transporters (OAT2, OAT3). Oatp1 and HLST transport bilirubin monoglucuronide. However, a transporter of unconjugated bilirubin in the sinusoidal membrane has not as yet been identified. Unconjugated bilirubin may also go across the hepatocyte sinusoidal membrane by a diffusion process. (2) Intrahepatic transport and conjugation of bilirubin: ligandin carries bilirubin to the endoplasmic reticulum (ER) of hepatocytes. In the ER, bilirubin is conjugated by bilirubin uridine diphosphate (UDP)-glycosyltransferase (bilirubin UGT; UGT1A1) to form mono- and diglucuronides of bilirubin. (3) Transport mechanism of bilirubin glucuronides across the hepatocyte canalicular membrane: at the canalicular membrane, bilirubin glucuronides are excreted into bile by multidrug resistance-associated protein 2 (MRP2), a member of the ATP-binding cassette transporter family. (4) Regurgitation of bilirubin glucuronides into blood: MRP3, which is located in the lateral membrane, transports bilirubin glucuronides into blood under conditions of impaired biliary bilirubin excretion.
Kamisako
T
T
Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osakasayama, Japan.
Kobayashi
Y
Y
Takeuchi
K
K
Ishihara
T
T
Higuchi
K
K
Tanaka
Y
Y
Gabazza
E C
EC
Adachi
Y
Y
D027321:Anion Transport Proteins; D001663:Bilirubin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D014535:Uridine Diphosphate Glucuronic Acid; C016266:bilirubin glucuronate; D001663:Bilirubin