The Role of Canalicular ABC Transporters in Cholestasis

Abstract

Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

“…About 95% of the bile salts travel through this cycle. A critical step in this process is the hepatic secretion of the bile, which is conducted by the transporters residing in the canalicular membrane of hepatocytes [2]. BSEP expels bile salts to the bile canaliculi, whereas MDR3/ABCB4 flips phosphatidyl choline (PC) to the outer leaflet of the membrane, resulting in net efflux of PC.…”

“…The ABCG5/G8 heterodimer exports cholesterol to mixed micelles and PC vesicles. Other canalicular transporters including ATP8B1/FIC1, MRP2/ABCC2, MDR1/ABCB1, ABCG2, and the chloride-bicarbonate anion exchanger 2 (AE2) also contribute to the composition of bile by retaining aminophospholipids and exporting divalent bile salts, anionic conjugates, organic cations, glutathione, and bicarbonate to the bile (reviewed in [2,25]). It has been proposed that ABCG2 is capable of bile acid transport [26], however, its physiological role, especially in the liver, is debated as discussed in detail in Ref.…”

“…The bile salt export pump (BSEP) is a liver resident transporter protein, which plays an essential role in the enterohepatic circulation of the bile salts [1,2]. BSEP belongs to the ATP-Binding Cassette (ABC) protein family, the members of which are integral membrane proteins, defined by the existence of conserved sequences, the Walker A, Walker B, and the so called ABC signature motif.…”

Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis

“…(NH), progressive familial intrahepatic cholestasis (PFIC), inborn errors of BA metabolism (IEBAM), and other metabolic or toxic insults (7)(8)(9). Prognosis of cholestasis patients is highly variable among the different disease entities and is difficult to predict during the early stage of disease.…”

The Role of Transporters in Toxicity and Disease

“…Integrating this knowledge is important to provide insight into hepatic inflammation, fibrosis, and cirrhosis. To address the role of transporters in the etiology of liver disease, in this issue, Cuperus et al (2014) provide an overview of the major canalicular ATP binding cassette (ABC) transporters and their regulation by nuclear receptors and function in cholestasis.…”