Enterohepatic Bile Acid Transporters In Liver Disease

Chronic cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis are characterized by an impairment of bile formation or of bile flow. Altered expression or function of bile acid transporters can be either a cause or a consequence of cholestasis, thus leading to hepatotoxicity due to accumulation of bile acids and cholephilic toxins in hepatocytes. Among the genes encoding transporters that are involved in bile acid transport or bile formation are several that have been identified or proposed as disease genes in the pathogenesis of cholestasis.

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by mutations in the ABCB11 gene, which encodes BSEP.24'25 These mutations in the ABCB11 gene lead to a rapidly progressive hepatic dysfunction in early infancy. In such patients the biliary bile salt levels can be reduced to less than 1% that of normal subjects. In a recent case report, specific ABCB11 mutations identified in an adolescent cholestatic patient correlated with reduced BSEP protein expression in vivo and decreased bile acid transport activity in vitro.26 Another case report suggested that heterozygous BSEP deficiency may predispose to transient neonatal cholestasis.27 Furthermore, defective or altered function or expression of BSEP may contribute to certain types of drug-induced cholestasis28 and may be associated with intrahepatic cholestasis of pregnancy.29

Defective MDR3 expression has also been associated with the inherited liver disease PFIC, type 3.30'31 PFIC3 is characterized by high bile acid concentrations and elevated 7 -glutamyl transpeptidase activity in serum. Several PFIC3-associated mutations in the ABCB4 gene may lead to either absent or severely decreased MDR3 expression at the canalicular membrane of hepatocytes. Similar to BSEP, there is increasing evidence suggesting that deficiency of impaired activity of MDR3 may be involved in cholestasis induced by drugs such as oral contraceptives.32'33

Inherited mutations in the ABCC2 gene encoding the canalicular transporter MRP2 are linked to the Dubin-Johnson syndrome, characterized by reduced efflux of conjugated bilirubin into bile.34-37 Some of these mutations have been reported to result in an absence of the MRP2 protein from the canalicular membrane of hepatocytes. In contrast to the PFIC syndromes, hepatic function is preserved in the Dubin-Johnson syndrome.

Mutations in the SLC10A2 gene encoding ASBT have been identified that can cause primary bile acid malabsorption, a rare disorder of the intestine characterized by congenital diarrhoea, steatorrhea and reduced plasma cholesterol levels.38 The ASBT variants carrying these mutations exhibit severely reduced bile acid transport activity in vitro.

No mutations in the SLC10A1 gene encoding NTCP leading to clinically manifest defects in hepatic bile acid uptake have been characterized thus far. However, a recent study identified ethnicity-dependent single-nucleotide polymorphisms in the SLC10A1 gene that were associated with a considerable decrease in transport function in vitro.39 Thus, genetic heterogeneity in the SLC10A1 gene may play a role in the etiology of hypercholanemia. Furthermore, certain human diseases, such as advanced stage primary biliary cirrhosis40 and cholestatic alcoholic hepatitis,41 are associated with reduced NTCP expression. However, this change in NTCP expression may be a consequence of cholestatic liver injury rather than a cause of it.

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