FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model

Non-alcoholic steatohepatitis (NASH) represents a major economic burden and is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat this condition. Emerging data suggests an important role of autophagy in this condition, which serves to degrade intracellular lipid stores, reduce hepatocellular damage, and dampen inflammation. Autophagy is primarily regulated by the transcription factors TFEB and TFE3, which are negatively regulated by mTORC1. Given that FLCN is a mTORC1 activator, we generated a liver-specific Flcn knockout mouse model to study its role in NASH progression. We demonstrate that loss of FLCN results in reduced triglyceride accumulation, fibrosis, and inflammation in mice exposed to a NASH-inducing diet. Furthermore, this study identifies a potential mechanism for NASH protection through autophagy activation resulting from the loss of FLCN. These results show an unexpected role for FLCN in NASH progression and highlight new possibilities for treatment strategies through its role in hepatocyte homeostasis. Overall design: RNA sequencing data from livers of 3-months old Alb-cre WT (Cre) and Alb-cre FLCN KO (FLCN KO) mice, fed either on chow or methionine/choline deficient diet (MCD) for six weeks