Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance

Abstract

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.

Life-Long Correction of Hyperbilirubinemia with a Neonatal Liver-Specific AAV-Mediated Gene Transfer in a Lethal Mouse Model of Crigler–Najjar Syndrome

“…Normally, these steps are performed by active transporters in the liver (Kamisako et al, 2000;Thomas et al, 2008). Thus, we evaluated, by semiquantitative RT-PCR, the expression of different transporters known to export conjugated/unconjugated bilirubin from hepatocytes (Fig.…”

“…This striking difference in the therapeutic effect between liver and skeletal muscle apparently resides in the liverspecific expression of Mrp2 and/or Mrp3 transporters (also known as Abcc2 and Abcc3, respectively), which extrude conjugated bilirubin from the hepatocyte to the bile and blood, respectively (Kamisako et al, 2000). Taken together, our data strongly support the concept that the liver is the most suitable target organ for efficient CNSI gene therapy and suggest that the potential use of extrahepatic tissues should be directly related to the presence of bilirubin transporters.…”

Mesoporous carbon biomaterials

“…In addition, their excellent biocompatibility and chemical/mechanical stability allow them to adsorb toxic pathogenic substances in vivo. We demonstrated that HMCNs could act as a clinical adsorbent for bilirubin [90], which can cause crippling, athetoid cerebral palsy and even death if overproduced [91]. Various absorbents such as activated carbon, chitosan, resins, and porous TiO 2 have been employed as adsorption materials in hemoperfusion columns to remove bilirubin from the blood [90].…”

Hepatic jaundice - a review

“…[6] Levels of bilirubin in blood are normally below 1.0 mg/dL (17 51 µmol/L) typically results in jaundice. [7][4] High bilirubin is divided into two types: unconjugated (indirect) and conjugated (direct). [8] Conjugated bilirubin can be confirmed by finding bilirubin in the urine.…”

“…[10] Among newborns, depending on age and prematurity, a bilirubin greater than 4-360 µmol/L) may be treated with phototherapy or exchanged transfusion. [7] The itchiness may be helped by draining the gallbladder or ursodeoxycholic acid. [3] The word jaundice is from the French jaunisse, meaning "yellow…”