ATPase Class I Type 8B Member 1 and protein kinase C zeta induce the expression of the canalicular bile salt export pump in human hepatocytes.
The exact molecular mechanism(s) of the disease that results from defects in the ATPase Class I Type 8B Member 1 gene remains controversial. Prior investigations of human ileum and in intestinal and ovarian cell lines have suggested that familial intrahepatic cholestasis 1 (FIC1) activates the farnesoid X-receptor (FXR) via a pathway involving protein kinase C zeta (PKCzeta). Translational investigations of human liver from individuals with FIC1 disease have been confounded by secondary affects of progressive cholestatic liver disease and limited numbers of samples for analysis. These studies, performed in primarily derived human hepatocytes, circumvent this issue. The canalicular bile salt export pump (BSEP) served as a downstream target of FXR. The siRNA-mediated silencing of FIC1 in human hepatocytes led to a reduction in both human BSEP promoter activity and BSEP protein expression, which correlated with a reduction in FXR expression and redistribution of its localization from the nucleus to the cytoplasm. These changes in BSEP expression could be reproduced by altering the expression of PKCzeta, with a positive correlation of PKCzeta activity and BSEP expression. Overall, these findings support the hypothesis that FIC1 enhances FXR signaling via a PKCzeta-dependent signaling pathway.
Chen
Frank
F
Children's Hospital of Pittsburgh of UPMC and the Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
Ellis
Ewa
E
Strom
Stephen C
SC
Shneider
Benjamin L
BL
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D000099221:Protein Kinase C zeta; D000099150:Receptor, Farnesoid X-Activated
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D011493:Protein Kinase C; D018160:Receptors, Cytoplasmic and Nuclear; D000099221:Protein Kinase C zeta; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C111067:ATP8B1 protein, human