Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.

• Authors: Mathieu Paquette, Ming Yan, Josué M J Ramírez-Reyes, Leeanna El-Houjeiri, Marco Biondini, Catherine R Dufour, Hyeonju Jeong, Alain Pacis, Vincent Giguère, Jennifer L Estall, Peter M Siegel, Étienne Audet-Walsh, Arnim Pause
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 21268 (10 28 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34711912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Bhd protein, mouse
• Biomarkers
• Proto-Oncogene Proteins
• Tumor Suppressor Proteins

Topics

• Animals
• Autophagy (genetics)
• Biomarkers
• Biopsy
• Computational Biology
• Diet, High-Fat
• Disease Models, Animal
• Disease Susceptibility
• Gene Expression Profiling
• Genetic Predisposition to Disease
• Hepatitis (etiology, metabolism, pathology)
• Immunohistochemistry
• Liver Cirrhosis (etiology, metabolism, pathology)
• Mice
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease (etiology, metabolism, pathology)
• Proto-Oncogene Proteins (deficiency)
• Signal Transduction
• Transcriptome
• Tumor Suppressor Proteins (deficiency)