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Abstract
Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosyltransferase to increase cysteine pool that drives the production of coenzyme A and glutathione, which support metabolic adaptation and antioxidant defense during increased lipid influx. Intriguingly, mice consuming an isocaloric protein-deficient Western diet exhibit selective hepatic cysteine, coenzyme A and glutathione deficiency and acylcarnitine accumulation, which are reversed by cystine supplementation without normalizing dietary protein intake. These findings support a pathogenic link of dysregulated sulfur amino acid metabolism to metabolic inflexibility that underlies both overnutrition and protein malnutrition-associated fatty liver development.
Matye el al. show that coenzyme-A and glutathione deficiency in NAFLD limits fatty acid oxidation and antioxidant defence capacity. The nutrient sensing transcription factor EB induces autophagy–lysosome proteolysis and methionine cycle-transsulfuration to maintain hepatic cysteine, coenzyme-A and glutathione availability.
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1 University of Oklahoma Health Sciences Center, Harold Hamm Diabetes Center, Department of Physiology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics, Kansas City, USA (GRID:grid.412016.0) (ISNI:0000 0001 2177 6375)
2 University of Kansas Medical Center, Department of Cell Biology and Physiology, Kansas City, USA (GRID:grid.412016.0) (ISNI:0000 0001 2177 6375)
3 University of Oklahoma Health Sciences Center, Harold Hamm Diabetes Center, Department of Physiology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618)
4 University of Oklahoma Health Sciences Center, Laboratory for Molecular Biology and Cytometry Research, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618)
5 University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics, Kansas City, USA (GRID:grid.412016.0) (ISNI:0000 0001 2177 6375)
6 Cedars-Sinai Medical Center, Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Los Angeles, USA (GRID:grid.50956.3f) (ISNI:0000 0001 2152 9905)