Abstract
The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of pregnancy (ICP). Over the past few years, several small molecular weight compounds have been identified, which hold the potential to treat these genetic diseases (chaperones and potentiators). As the treatment response is mutation-specific, genetic analysis of the patients and their families is required. Furthermore, some of the mutations are refractory to therapy, with the only remaining treatment option being liver transplantation. In this review, we will focus on the molecular structure of ABCB11, reported mutations involved in cholestasis and current treatment options for inherited BSEP deficiencies.
Highlights
The ATP-binding cassette (ABC) proteins constitute one of the largest families of membrane proteins
Wang et al used this model system to suggest that P-glycoprotein (ABCB1) can act as a compensatory bile salt transporter, which alleviates the severity of cholestasis in bile salt export pump (BSEP) knockout mice [94]
Despite the relative infrequency of the inherited forms of progressive intrahepatic cholestasis, the symptoms are severe, and about half of the patients progress to a stage of the disease that makes them candidates for liver transplantation
Summary
The ATP-binding cassette (ABC) proteins constitute one of the largest families of membrane proteins. 48 functional genes encode for ABC proteins, which on the basis of structural and sequence similarity are categorized into seven subfamilies, designated as ABCA through G [1] Most of these proteins transport substrates across cellular membranes. Expression of BSEP is regulated by a major ligand-activated transcription factor, farnesoid X receptor (FXR, NR1H4), which forms a signaling-competent nuclear receptor heterodimer with the retinoid X receptor (RXR) (Figure 2). The FXR/RXR heterodimer binds to an FXR response element (FXRE) in the promoter region of BSEP, thereby inducing the expression of the transporter [20]. Nrf regulates the expression of BSEP, and that of a number of hepatic phase I and II enzymes and other hepatic efflux transporters such as MRP3 (ABCC3) and MRP4 (ABCC4) [26]
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