The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor.

[benign recurrent intrahepatic cholestasis]

Prior loss -of-function analyses revealed that ATPase class I type 8 B member 1 [familial intrahepatic cholestasis 1 (FIC 1 )] posttranslationally activated the farnesoid X receptor (FXR ). Mechanisms underlying this regulation were examined by gain-of-function studies in UPS cells , which lack endogenous FIC 1 expression . FXR function was assayed in response to wild-type and mutated FIC 1 expression constructs with a human bile salt export pump (BSEP ) promoter and a variety of cellular localization techniques . FIC 1 overexpression led to enhanced phosphorylation and nuclear localization of FXR that was associated with FXR-dependent activation of the BSEP promoter . The FIC 1 effect was lost after mutation of the FXR response element in the BSEP promoter . Despite similar levels of FIC 1 protein expression , Byler disease FIC 1 mutants did not activate BSEP , whereas benign recurrent intrahepatic cholestasis mutants partially activated BSEP . The FIC 1 effect was dependent on the presence of the FXR ligand , chenodeoxycholic acid . The effect of FIC 1 on FXR phosphorylation and nuclear localization and its effects on BSEP promoter activity could be blocked with protein kinase C zeta (PKC zeta ) inhibitors (pseudosubstrate or small interfering RNA silencing ). Recombinant PKC zeta directly phosphorylated immunoprecipitated FXR . The mutation of threonine 442 of FXR to alanine yielded a dominant negative protein , whereas the phosphomimetic conversion to glutamate resulted in FXR with enhanced activity and nuclear localization . Inhibition of PKC zeta in Caco-2 cells resulted in activation of the human apical sodium-dependent bile acid transporter promoter .These results demonstrate that FIC 1 signals to FXR via PKC zeta . FIC 1 -related liver disease is likely related to downstream effects of FXR on bile acid homeostasis . Benign recurrent intrahepatic cholestasis emanates from a partially functional FIC 1 protein . Phosphorylation of FXR is an important mechanism for regulating its activity .

Diseases
Validation

Diseases presenting "intrahepatic cholestasis" symptom

benign recurrent intrahepatic cholestasis

zellweger syndrome

This symptom has already been validated