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

Paquette, M.; Yan, M.; El-Houjeiri, L.; Biondini, M.; Ramirez-Reyes, J. M. J.; Pacis, A.; Jeong, H.; Estall, J. L.; Siegel, P. M.; Pause, A.

doi:10.1101/2020.09.10.291617

bioRxiv · 10.1101/2020.09.10.291617

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

Paquette, M.·Yan, M.·El-Houjeiri, L.·Biondini, M.·Ramirez-Reyes, J. M. J.·Pacis, A.·Jeong, H.·Estall, J. L.·Siegel, P. M.·Pause, A.

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Abstract

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 an mTORC1 activator via its GAP activity towards RagC/D, 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. Hence, the GAP activity of FLCN could a promising target for small molecule drugs to treat NASH progression by specifically activating autophagy and lysosomal biogenesis while leaving mRNA translation machinery unperturbed. Collectively, these results show an unexpected role for FLCN in NASH progression and highlight new possibilities for treatment strategies through its role in hepatocyte homeostasis.

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Paquette, M., Yan, M., El-Houjeiri, L., Biondini, M., Ramirez-Reyes, J. M. J., Pacis, A., Jeong, H., Estall, J. L., Siegel, P. M., Pause, A.. 2020-09-11. FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model. https://doi.org/10.1101/2020.09.10.291617

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