ABCB4

ABCB4, also known as MDR3, is a human gene encoding an ATP-binding cassette (ABC) transporter of the B subfamily. The encoded protein functions as a canalicular phospholipid transporter in hepatocytes, using ATP hydrolysis to translocate phosphatidylcholine into bile. Secretion of phosphatidylcholine into bile is essential for forming bile micelles, reducing bile salt toxicity, and protecting cholangiocytes and the canalicular membrane from bile acid–induced injury. ABCB4 expression is highest in the liver, with limited expression in other tissues.

Genetics and disease: ABCB4 mutations cause a spectrum of cholestatic liver diseases, most notably progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disorder presenting with early-onset cholestasis, pruritus, hepatomegaly, and potential progression to fibrosis. Heterozygous ABCB4 variants have been associated with low phospholipid-associated cholelithiasis (LPAC) and, in some cases, intrahepatic cholestasis of pregnancy (ICP).

Clinical management: Diagnosis is achieved through genetic testing in the setting of cholestasis. First-line medical therapy for PFIC3-related cholestasis is ursodeoxycholic acid; rifampin or other antipruritic approaches may be used for intractable itch. In severe or progressive cases, liver transplantation may be required.

Structure and mechanism: ABCB4 encodes a half-transporter that forms functional dimers. It belongs to the ABC transporter family, specifically the MDR subfamily. Disruption of PC transport by ABCB4 mutations alters bile composition, increasing bile acid–induced injury and contributing to cholestasis.