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Chem Biol Interact. 2019 Apr 25;303:1-6. doi: 10.1016/j.cbi.2019.02.015. Epub 2019 Feb 20.

Hepatic metabolic adaptation in a murine model of glutathione deficiency.

Author information

1
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA. Electronic address: ying.chen@yale.edu.
2
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, 20852, USA.
3
Bioinformatics Support Program, Yale School of Medicine, New Haven, CT, 06521, USA.
4
Department of Clinical Pharmacology, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, 80045, USA.
5
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA. Electronic address: vasilis.vasiliou@yale.edu.

Abstract

Glutathione (GSH), the most abundant cellular non-protein thiol, plays a pivotal role in hepatic defense mechanisms against oxidative damage. Despite a strong association between disrupted GSH homeostasis and liver diseases of various etiologies, it was shown that GSH-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice are protected against fatty liver development induced by a variety of dietary and environmental insults. The biochemical mechanisms underpinning this protective phenotype have not been clearly defined. The purpose of the current study was to characterize the intrinsic metabolic signature in the livers from GSH deficient Gclm-null mice. Global profiling of hepatic polar metabolites revealed a spectrum of changes in amino acids and metabolites derived from fatty acids, glucose and nucleic acids due to the loss of GCLM. Overall, the observed low GSH-driven metabolic changes represent metabolic adaptations, including elevations in glutamate, aspartate, acetyl-CoA and gluconate, which are beneficial for the maintenance of cellular redox and metabolic homeostasis.

KEYWORDS:

Fatty liver disease; Glutamate cysteine ligase; Glutathione; Metabolomics; Steatosis

PMID:
30794799
DOI:
10.1016/j.cbi.2019.02.015
[Indexed for MEDLINE]

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