Elucidating ATP8B1 Deficiency Using Genetic Modifiable Patient-Derived iPSC-livers

About This Grant

PROJECT SUMMARY Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, inherited liver diseases that impair bile formation and excretion, leading to severe cholestasis, progressive liver damage, and, often, the need for liver transplantation in childhood. ATP8B1 deficiency, previously known as PFIC1, caused by mutations in the ATP8B1 gene, remains poorly understood due to the lack of suitable animal models and the rarity of the disorder. Current treatment strategies focus on reducing enterohepatic bile acid circulation but fail to prevent ongoing hepatocellular injury. The ATP8B1 protein (FIC1) maintains canalicular membrane asymmetry and modulates bile acid signaling through the farnesoid X receptor (FXR), but how its loss-of-function causes cholestasis is incompletely understood. Using patient-derived induced pluripotent stem cells (iPSCs) carrying the common ATP8B1 G308V mutation, our group has established clinically relevant hepatocyte and cholangiocyte models that recapitulate disease phenotypes. Preliminary studies reveal alterations in plasma membrane organization, FXR activation, glutamine metabolism, and cholangiocyte protective mechanisms. This proposal will test the central hypothesis that ATP8B1 G308V disrupts bile acid homeostasis and cellular resilience through impaired FXR activity, altered glutamine metabolism, and reduced cholangiocyte protection, leading to cholestasis and progressive liver pathology. Specifically, we will i) define how FIC1 deficiency and FXR suppression contribute to bile acid accumulation and hepatocyte vulnerability, ii) interrogate the role of glutamine metabolism in bile acid dysregulation and determine whether supplementation restores hepatocyte function, and iii) evaluate how restoring MUC1 expression improves cholangiocyte function and hepatobiliary homeostasis. The proposed studies will generate new mechanistic insights into ATP8B1 deficiency, provide a unique patient- derived model for studying rare cholestatic diseases, and identify molecular pathways that can be targeted for therapeutic intervention. Ultimately, this work will inform strategies not only for PFIC1 but also for other cholestatic and metabolic liver diseases of genetic origin.