ABCB4, also known as multidrug resistance protein 3 (MDR3), is a member of the ATP-binding cassette transporter superfamily. It is localized at the canalicular membrane of hepatocytes and is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane, protecting the hepatobiliary system from the harsh detergent activity of bile salts and ensuring cholesterol solubilization in bile [1,2,3,4,5]. This process is crucial for bile formation and maintaining the integrity of the biliary tree [2].

ABCB4 deficiency, often caused by gene mutations, leads to various liver and gallbladder diseases. In ABCB4 knockout mice, a model for low-phospholipid associated cholelithiasis (LPAC), the gallbladder bile has only trace amounts of phospholipids, is supersaturated with cholesterol, and shows “anhydrous” cholesterol crystallization, similar to the human LPAC phenotype [6]. These mice help reveal that ABCB4 mutations are the genetic basis of LPAC, which is characterized by reduced phospholipids in bile, symptomatic cholelithiasis at a young age, and intrahepatic sludge [6].

In conclusion, ABCB4 is vital for biliary phospholipid secretion and maintaining the normal function of the hepatobiliary system. Studies using ABCB4 knockout mouse models have been instrumental in understanding the pathogenesis of LPAC and other related cholestatic diseases, highlighting the importance of ABCB4 in preventing abnormal cholesterol crystallization and bile-related disorders [6].

References:

1. Sticova, Eva, Jirsa, Milan. 2019. ABCB4 disease: Many faces of one gene deficiency. In Annals of hepatology, 19, 126-133. doi:10.1016/j.aohep.2019.09.010. https://pubmed.ncbi.nlm.nih.gov/31759867/

2. Prescher, Martin, Kroll, Tim, Schmitt, Lutz. . ABCB4/MDR3 in health and disease - at the crossroads of biochemistry and medicine. In Biological chemistry, 400, 1245-1259. doi:10.1515/hsz-2018-0441. https://pubmed.ncbi.nlm.nih.gov/30730833/

3. Reichert, Matthias Christian, Lammert, Frank. 2018. ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum. In Seminars in liver disease, 38, 299-307. doi:10.1055/s-0038-1667299. https://pubmed.ncbi.nlm.nih.gov/30357767/

4. Stättermayer, Albert Friedrich, Halilbasic, Emina, Wrba, Fritz, Ferenci, Peter, Trauner, Michael. 2020. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. In Journal of hepatology, 73, 651-663. doi:10.1016/j.jhep.2020.04.036. https://pubmed.ncbi.nlm.nih.gov/32376413/

5. Falguières, Thomas, Aït-Slimane, Tounsia, Housset, Chantal, Maurice, Michèle. 2014. ABCB4: Insights from pathobiology into therapy. In Clinics and research in hepatology and gastroenterology, 38, 557-63. doi:10.1016/j.clinre.2014.03.001. https://pubmed.ncbi.nlm.nih.gov/24953525/

6. Wang, Helen H, Portincasa, Piero, Liu, Min, Wang, David Q-H. 2022. Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis. In Genes, 13, . doi:10.3390/genes13061047. https://pubmed.ncbi.nlm.nih.gov/35741809/