CFTR correctors enhance ATP8B1 I661T plasma membrane expression. A novel treatment for ATP8B1 deficiency?

Abstract

Mutations in the ATP8B1 gene can cause benign recurrent intrahepatic cholestasis 1 (BRIC1) or progressive familial intrahepatic cholestasis 1 (PFIC1), commonly known as ATP8B1 deficiency. ATP8B1 is an aminophospholipid flippase, maintaining membrane asymmetry. In ATP8B1 deficiency the activity of the bile salt export pump (BSEP) which pumps bile salts out of the hepatocytes into the bile duct is decreased, leading to accumulation of bile salts and cell damage. However, the mechanism by which ATP8B1 defects causes cholestasis is unknown. Involvement of the nuclear receptor FXR or reduced membrane stability and consequent decreased BSEP activity have been suggested. Proper ATP8B1 folding and association with CDC50A is required for ATP8B1 to exit the ER and traffic to the plasma membrane. It was recently demonstrated that ATP8B1 mutations often result in protein misfolding and subsequent ER retention and protein degradation. Molecular chaperones facilitate protein folding and trafficking. The cystic fibrosis conductance regulator (CFTR) is frequently mutated causing cystic fibrosis due to misfolding of this chloride channel. Several pharmacological chaperones enhance CFTR plasma membrane expression. Therefore, the effect of three of these chaperones was tested on mutant ATP8B1 (I661T) expression. Corrector C1 showed the best result and enhanced total and cell surface ATP8B1 I661T expression by 25% and 90% respectively. This suggests that C1 particularly enhances trafficking of ATP8B1 I661T to the plasma membrane. Pharmacological treatment with this chaperone might be an effective therapeutic treatment to relieve the symptoms of BRIC1 patients that often have an I661T mutation.