Significant technological advances in gene sequence analysis and construction of genetically-modified animals during the last two decades made it possible to reveal that many transporters are associated with diseases. The
bile salt export pump (BSEP/ABCB11), a member of the family of
ATP-binding cassette transporters, is localized on the canalicular membrane of hepatocytes and predominantly mediates the biliary excretion of
bile salts. A hereditary defect of BSEP results in severe
cholestasis called
progressive familial intrahepatic cholestasis type 2 (PFIC2). Without
liver transplantation, this disease progresses to
liver failure and death before adulthood; therefore the development of new, less invasive medical
therapy for PFIC2 is of the highest priority. We have previously shown that in many cases of PFIC2 patients, the dysfunction of BSEP is attributable to decreased BSEP expression on the hepatocanalicular membrane and that
4-phenylbutyrate (4PB), an approved drug for
urea cycle disorder, may be a compound with potential to restore BSEP expression. This drug inhibits ubiquitination of cell surface-resident BSEP and thereby its
clathrin-mediated endocytosis through the AP2 adaptor complex, leading to increase in BSEP expression on the canalicular membrane. Clinical studies to investigate the efficacy of 4PB in the treatment of PFIC2 revealed that 4PB
therapy biochemically and histologically improved liver function without any side effect. Therefore, 4PB
therapy may become the preferred choice, instead of
liver transplantation, for PFIC2 patients. The strategy employed and findings in this study would be valuable for the drug development of transporter-related disorders.