ABCB11

Official Full Name

ATP binding cassette subfamily B member 11

Organism

Homo sapiens

GeneID

8647

Background

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008]

Synonyms

BSEP; PGY4; SPGP; ABC16; BRIC2; PFIC2; PFIC-2;

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Detailed Information

The protein expressed by the ABCB11 (ATP binding cassette, sub-family B member 11) gene is also called a bile salt export pump (BESP). The ABCB11 gene belongs to the ATP binding cassette (ABC) transporter family, which is mainly expressed in the liver tissue. Its two transmembrane domains (TMD) and two nucleotide domains (NBD) constitute a classical ABC transporter.

ABCB11 is a special glycoprotein in the liver. By the consumption of ATP, hepatic bile duct cells secrete bile salts in hepatocytes into the bile duct to form bile. In this process, BESP plays a vital role. The encoded expression of the ABCB11 gene is highly regulated by the farnesoid X receptor (FXR) and the retinoid X receptor α-heterodimer (RXR). FXR is an important transcription factor regulated by bile acids, and the synthesis and transport of bile acids are regulated by it. BESP is recruited to the vesicle apical membrane of hepatocytes and binds to pathways that have cAMP and regulate PI3K signaling, thereby reducing intracellular osmotic pressure leading to hepatocyte swelling and bile acid secretion. BESP is mainly involved in the delivery of monovalent bile salts, including bile acids (CA) and chenodeoxycholic acid (CDCA), secondary bile acid deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA).

Abnormal Expression of ABCB11 Gene Forms Cholestasis

Changes in the ABCB11 gene directly affect its protein expression and function and are associated with a variety of cholestatic liver and gallbladder diseases. Human genome sequencing revealed familial intrahepatic cholestasis caused by abnormal expression of the ABCB11 gene. It usually occurs in infancy and is called progressive familial intrahepatic cholestasis type II (PFIC2), an autosomal recessive genetic disorder. This finding confirms that BESP is identified as a determinant of bile salt-dependent bile flow. Additional mutations and polymorphisms in ABCB11 were also found to indicate that significant changes in the ABCB11 gene result in altered function of the BESP leading to liver disease. This series of mild to severe lesions gradually formed a cholestasis called the BESP deficiency syndrome.

Other studies have also suggested that the clinical pathological changes of PFIC2 characterized by low glutamate transpeptidase (GGT) are associated with genetic changes in hepatocytes ABCB11 and ATP8B1. A lesion similar to PFIC2 is called benign recurrent intrahepatic cholestasis (BRIC2), which is a slightly stable disease and is an autosomal recessive genetic disorder that can occur at any age. The main clinical manifestations are recurrent episodes of jaundice and itching. The course of disease can last for several weeks and can be relieved by itself, but it can develop into PFIC2 after severe disease. At the same time, some scholars have also proposed that the clinical pathological changes of PFIC2 characterized by low glutamate transpeptidase (GGT) are related to the genetic changes of hepatocytes ABCB11 and ATP8B1. Lai et al. found that there are other types of cholestasis in the clinic. For example, cholestasis during pregnancy is also closely related to changes in ABCB11 gene expression, suggesting that this acquired physiological factor during pregnancy may inhibit the function of BESP and cause cholestasis.

Figure 1. The role of ABCB11 and BSEP in cholestasis. (Erlinger. 2015).

Hirobejahn et al. found that the ABCB11 gene plays a crucial role in the formation of bile acids and the metabolism of bile acids. And it is regulated by the FXR gene. Once the FXR changes, it will cause changes in cholestasis and bile acid. The change of the ratio of bile salts will reduce the dissolution of cholesterol and lead to the precipitation of cholesterol. This is an important risk factor for the formation of gallstones. It can be seen that changes in the ABCB11 gene cause intrahepatic bile duct cholestasis, which is bound to change bile acid composition, thus forming favorable conditions for gallstones.

ABCB11 Gene Alteration is A Direct Factor in Gallstone Formation

The study found that the bile salt export pump gene ABCB11 gene maps to the Light1 locus. Moreover, during the experiment, the overexpression of mouse BESP revealed that the cholesterol absorption of the mice increased and the cholesterol crystals increased in the bile, which greatly increased the probability of gallstone cholesterol stones. This study strongly supports ABCB11 as a gene that causes stones. The main role of ABCB11 protein is to participate in the secretion of bile. However, high expression of mice promotes the formation of food-borne obesity and hypercholesterolemia because of increased intestinal cholesterol absorption of hydrophobic bile acids and increased absorption of intestinal fat. Therefore, this ABCB11 gene overexpresses a series of expression processes to create a basis for the accelerated formation of gallstone cholesterol stones.

Kong et al. found that the relationship between BESP and PKCα and HAX-1 in the C57L mice fed a high cholesterol diet and on the hepatic tubular membrane was found to be related to the down-regulation of BESP expression. The interaction between BESP and HAX-1 has also increased. In a clinical statistical study, Condat et al. found that more than half of patients with cholelithiasis who did not exceed 18 years of age provided ABCB11 gene abnormalities. Some researchers have suggested that bile pigment stones have a certain correlation with ABCB11 and ABCC2 genes on hepatic bile ducts. The transport protein of the hepatic bile duct lateral membrane changes the bile secretion function and promotes the bile pigmentation. However, some scholars have studied the overexpression of mouse ABCB11 gene and found that excessive ABCB11 gene expression significantly promoted the increase of bile salts and circulating bile flow, while cholesterol and phospholipid secretion and gallbladder size and contraction were similar to the control group. The study suggests that the ABCB11 gene may not have much effect on cholesterol stones, and the results of this study have not been verified.

References:

Lai, Y. (2013). Transporters in Drug Discovery and Development: Detailed Concepts and Best Practice. Transporters in Drug Discovery and Development.
Hirobejahn, S., Harsch, S., Renner, O., Richter, D., Müller, O., & Stange, E. F. (2015). Association of fxr gene variants with cholelithiasis. Clinics & Research in Hepatology & Gastroenterology, 39(1), 68-79.
Kong, J., Liu, B. B., Wu, S. D., Wang, Y., Jiang, Q. Q., & Guo, E. L. (2014). Enhancement of interaction of bsep and hax-1 on the canalicular membrane of hepatocytes in a mouse model of cholesterol cholelithiasis. Int J Clin Exp Pathol, 7(4), 1644-1650.
Condat, B., Zanditenas, D., Barbu, V., Hauuy, M. P., Parfait, B., & El, N. A., et al. (2013). Prevalence of low phospholipid-associated cholelithiasis in young female patients. Dig Liver Dis, 45(11), 915-919.
Erlinger, S. (2015). Genetic cholestatic diseases. Textbook of Hepatology: From Basic Science to Clinical Practice, Third Edition. Blackwell Publishing Ltd.

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