ABCB4 Membrane Protein Introduction

Introduction of ABCB4

ABCB4 encoded by ABCB4 gene is a member of the superfamily of ATP-binding cassette (ABC) transporters which transport various molecules across extra- and intracellular membranes. There are seven subfamilies in ABC superfamily named as ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White, respectively. ABCB4 protein belongs to MDR/TAP subfamily which is involved in the regulation of multidrug resistance and antigen presentation. The topology of ABCB4 shows a high homology to ABCB1 with 12 membrane-spanning domains. However, the two proteins serve as different functions.

Function of ABCB4 Membrane Protein

ABCB4 is primarily expressed on the hepatocyte canalicular membrane where it serves as a phosphatidylcholine flippase mediating the transport of phosphatidylcholine (PC) from inner lipid leaflet of the bile canaliculus to the outer leaflet. The process replenishes the phospholipid which is continuously removed into the bile because of contact with bile acids. The deficiency of ABCB4 lead to the high bile acid-phospholipid ratios that damage the canalicular membrane, resulting in progressive destruction of small bile ducts and a wide spectrum of hepatobiliary disorders. Mutations in ABCB4 are associated with small-duct primary sclerosing cholangitis, adult biliary cirrhosis, transient neonatal cholestasis, drug-induced cholestasis and intrahepatic cholestasis of pregnancy and cholesterol gallstone disease. Furthermore, the nonsense or missense mutations of ABCB4 gene also have been indicated an association with the progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare lethal autosomal recessive liver disease. Besides, ABCB4 plays a role in drug resistance. Taxanes are a class of anti-cancer drugs which can be eliminated from tumors by way of the ABC drug transporters such as ABCB4, thus changing the pharmaceutical effect.

Fig.1 Cooperation of BSEP, ABCB4 and MRP2 in the canalicular membrane of hepatocytes. (Montanari, 2015)

Application of ABCB4 Membrane Protein in Literature

1. Huang J.F., et al. Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro. Cancer Chemotherapy & Pharmacology. 2018: 1-12. PubMed ID: 29777275
   
   

   The study shows that ABCB4 regulates the efflux transport of doxorubicin and the overexpression of ABCB4 is responsible for the acquired doxorubicin resistance in breast cancer cells.

2. Gautherot J., et al. Thyroid hormone receptor β1 stimulates ABCB4 to increase biliary phosphatidylcholine excretion in mice. J Lipid Res. 2018. PubMed ID: 29895698
   
   

   The study indicates that thyroid hormone may be involved in the regulation of bile duct homeostasis through activating ABCB4 to increase biliary phosphatidylcholine excretion.

3. Sharma A., et al. Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis. BMC Gastroenterol. 2018, 18(1): 107. PubMed ID: 29973134
   
   

   The study identifies nine major genomic variations of ATP8B1, ABCB11 and ABCB4 genes in nearly 9 Indian children with progressive familial intrahepatic cholestasis (PFIC).

4. Hu H., et al. Loss of ABCB4 attenuates the caspase-dependent apoptosis regulating resistance to 5-Fu in colorectal cancer. Bioscience Reports. 2018, 192: 251-260. PubMed ID: 29371412
   
   

   The study indicates that the expression of ABCB4 is decreased in the 5-fluorouracil resistant cells and knockdown of ABCB4 relieves the cell apoptosis. Moreover, ABCB4 can predict a poor recurrence-free survival and overall survival in human colorectal cancer.

5. Vitale G., et al. Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2, gene variants analysis by high-throughput sequencing. Journal of Gastroenterology. 2018, 53(8): 945-958. PubMed ID: 29238877
   
   

   The study reveals that mutations in the ATP8B, ABCB11, ABCB4, and TJP2 genes may be associated with both young and adults with cryptogenic cholestasis.

ABCB4 Preparation Options

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Reference

1. Montanari F and Ecker G F. (2015). Prediction of drug-ABC-transporter interaction-Recent advances and future challenges. Advanced Drug Delivery Reviews. 86, 17-26.

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