Abstract
ATP-binding cassette (ABC) transporters are the members of the efflux pumps that are responsible for the removal of cytotoxic substances by active transport. ABCB11, the bile salt efflux pump of hepatocytes, coordinates cellular excretion of numerous conjugated bile salts into the bile canaliculi, whereas ABCB4 acts as an ATP-dependent floppase translocating phosphatidylcholine from the inner to the outer leaflet of the bile canalicular membrane. Loss of functional ABCB11 and ABCB4 proteins causes early-onset refractory cholestasis or cholangiopathy. In this study, we investigated the expression and localization pattern of ABCB11 and ABCB4 using immunohistochemistry and RNA profiling in liver samples from patients with different types and stages of chronic cholestatic liver disease, with emphasis on primary sclerosing cholangitis (PSC), compared to a variety of cholestatic and noncholestatic hepatopathies. Therefore, ABCB11 and ABCB4 expressions were investigated on formalin-fixed and paraffin-embedded (FFPE) material in a patient cohort of total 43 patients with or without cholestatic liver diseases, on protein level using immunohistochemistry and on RNA level using nanoString technology. Intriguingly, our results demonstrated increased expression of ABCB11 and ABCB4 on protein as well as RNA level in PSC, and the expression pattern correlated with disease progression. We concluded from our study that patients with PSC demonstrate altered expression levels and pattern of ABCB11 and ABCB4 which correlated with disease progression; thereby, ABCB11 and ABCB4 analysis may be a useful tool for assessment of disease stages in PSC.
Highlights
In normal hepatocytes, the bile release occurs at the canalicular membrane predominantly through the action of transporters belonging to the adenosine triphosphatebinding-cassette (ABC) family [1, 2]
Absence of ABCB11 and ABCB4 proteins related to mutations in the ABCB11 and ABCB4 gene causes PFIC2 and 3 and leads to severe cholestatic liver disease in children that results in development of progressive cholestasis and liver cirrhosis [1,2,3,4,5,6, 18,19,20]
In contrast to patients with cholestatic liver disease related to ABCB11 mutations, functional analysis of ABCB11 deficiency in rodents showed that ABCB11 deficient mice did not develop progressive cholestasis and were associated with a milder phenotype when compared to MDR2 deficient mice [18,19,20,21]
Summary
The bile release occurs at the canalicular membrane predominantly through the action of transporters belonging to the adenosine triphosphatebinding-cassette (ABC) family [1, 2]. ABCB11 is the main bile salt transporter in hepatocytes that is expressed at the apical membrane of hepatocytes, and when dysfunctional leads to various cholestatic disorders including. ABCB4 is expressed at the apical membrane of hepatocytes and is essential for phosphatidylcholine secretion into the bile. In PFIC, a dysfunctional ABCB4 protein leads to damage of bile canaliculi and small bile ducts and causes chronic and progressive liver disease [1,2,3,4,5,6]. PSC is a rare disorder characterized by chronic intra- and extrahepatic bile duct inflammation leading to progressive periductal fibrosis, multifocal bile duct strictures, dilatation (cholangiectasis), progressive cholestatic liver disease and hepatic dysfunction [11,12,13]
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