Defective ABCB4 causes progressive familial intrahepatic cholestasis 3, intrahepatic cholestasis of pregnancy 3 and gallbladder disease 1

Stable Identifier
R-HSA-5678771
Type
Pathway
Species
Homo sapiens
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Multidrug resistance protein 3 (ATP-binding cassette sub-family B member 4, ABCB4 aka MDR3) mediates the ATP-dependent export of organic anions, phospholipids and drugs from hepatocytes into the canalicular lumen in the presence of bile salts, especially the export of phospholipids such as phosphatidylcholine (PC). Biliary phospholipids associate with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallisation. Thus, ABCB4 plays a crucial role in bile formation and lipid homeostasis. Defects in ABCB4 result in a wide spectrum of cholestasis phenotypes, from progressive familial intrahepatic cholestasis 3 (PFIC3; MIM:602347) and intrahepatic cholestasis of pregnancy 3 (ICP3; MIM:614972) to gallbladder disease 1 (GBD1; MIM:600803) (Jacquemin et al. 2001, Davit-Spraul et al. 2010, Jacquemin 2012). In PFIC3, the biliary phospholipid level is substantially decreased despite the presence of bile acids. Cholestasis may be caused by the toxicity of detergent bile salts that are not associated with phospholipids, leading to bile canaliculus and biliary epithelium damage. ICP3 is a reversible form of cholestasis in the third trimester of pregnancy and quickly disappears after childbearing. GBD1 is one of the major digestive diseases. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations of GBD1 in western countries. Most people with gallstones remain asymptomatic throughout their lifetimes but approximately 10-50% of individuals eventually develop symptoms.

Literature References
PubMed ID Title Journal Year
11313315 The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood

Jacquemin, E, De Vree, JM, Cresteil, D, Sokal, EM, Sturm, E, Dumont, M, Scheffer, GL, Paul, M, Burdelski, M, Bosma, PJ, Bernard, O, Hadchouel, M, Elferink, RP

Gastroenterology 2001
20422496 The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects

Davit-Spraul, A, Gonzales, E, Baussan, C, Jacquemin, E

Semin. Liver Dis. 2010
23141890 Progressive familial intrahepatic cholestasis

Jacquemin, E

Clin Res Hepatol Gastroenterol 2012
Participants
Participant Of
Disease
Name Identifier Synonyms
intrahepatic cholestasis 1852 intrahepatic cholestasis of pregnancy
cholelithiasis 10211
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