TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis

David Matye, Sumedha Gunewardena, Jianglei Chen, Huaiwen Wang, Yifeng Wang, Mohammad Nazmul Hasan, Lijie Gu, Yung Dai Clayton, Yanhong Du, Cheng Chen, Jacob E. Friedman, Shelly C. Lu, Wen-Xing Ding and Tiangang Li ()
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David Matye: University of Oklahoma Health Sciences Center
Sumedha Gunewardena: University of Kansas Medical Center
Jianglei Chen: University of Oklahoma Health Sciences Center
Huaiwen Wang: University of Oklahoma Health Sciences Center
Yifeng Wang: University of Kansas Medical Center
Mohammad Nazmul Hasan: University of Oklahoma Health Sciences Center
Lijie Gu: University of Oklahoma Health Sciences Center
Yung Dai Clayton: University of Oklahoma Health Sciences Center
Yanhong Du: University of Oklahoma Health Sciences Center
Cheng Chen: University of Oklahoma Health Sciences Center
Jacob E. Friedman: University of Oklahoma Health Sciences Center
Shelly C. Lu: Cedars-Sinai Medical Center
Wen-Xing Ding: University of Kansas Medical Center
Tiangang Li: University of Oklahoma Health Sciences Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33465-9

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DOI: 10.1038/s41467-022-33465-9

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