TY - JOUR
T1 - Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis
AU - Chen, Ying
AU - Manna, Soumen K.
AU - Golla, Srujana
AU - Krausz, Kristopher W.
AU - Cai, Yan
AU - Garcia-Milian, Rolando
AU - Chakraborty, Tanushree
AU - Chakraborty, Joyeeta
AU - Chatterjee, Raghunath
AU - Thompson, David C.
AU - Gonzalez, Frank J.
AU - Vasiliou, Vasilis
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Depletion of glutathione (GSH) is considered a critical pathogenic event promoting alcohol-induced lipotoxicity. We recently show that systemic GSH deficiency in mice harboring a global disruption of the glutamate-cysteine ligase modifier subunit (Gclm) gene confers protection against alcohol-induced steatosis. While several molecular pathways have been linked to the observed hepatic protection, including nuclear factor erythroid 2-related factor 2 and AMP-activated protein kinase pathways, the precise mechanisms are yet to be defined. In this study, to gain insights into the molecular mechanisms underpinning the protective effects of loss of GCLM, global profiling of hepatic polar metabolites combined with liver microarray analysis was carried out. These inter-omics analyses revealed both low GSH- and alcohol-driven changes in multiple cellular pathways involving the metabolism of amino acids, fatty acid, glucose and nucleic acids. Notably, several metabolic changes were uniquely present in alcohol-treated Gclm-null mouse livers, including acetyl-CoA enrichment and diversion of acetyl-CoA flux from lipogenesis to alterative metabolic pathways, elevation in glutamate concentration, and induction of the glucuronate pathway and nucleotide biosynthesis. These metabolic features reflect low GSH-elicited cellular response to chronic alcohol exposure, which is beneficial for the maintenance of hepatic redox and metabolic homeostasis. The current study indicates that fine-tuning of hepatic GSH pool may evoke metabolic reprogramming to cope with alcohol-induced cellular stress.
AB - Depletion of glutathione (GSH) is considered a critical pathogenic event promoting alcohol-induced lipotoxicity. We recently show that systemic GSH deficiency in mice harboring a global disruption of the glutamate-cysteine ligase modifier subunit (Gclm) gene confers protection against alcohol-induced steatosis. While several molecular pathways have been linked to the observed hepatic protection, including nuclear factor erythroid 2-related factor 2 and AMP-activated protein kinase pathways, the precise mechanisms are yet to be defined. In this study, to gain insights into the molecular mechanisms underpinning the protective effects of loss of GCLM, global profiling of hepatic polar metabolites combined with liver microarray analysis was carried out. These inter-omics analyses revealed both low GSH- and alcohol-driven changes in multiple cellular pathways involving the metabolism of amino acids, fatty acid, glucose and nucleic acids. Notably, several metabolic changes were uniquely present in alcohol-treated Gclm-null mouse livers, including acetyl-CoA enrichment and diversion of acetyl-CoA flux from lipogenesis to alterative metabolic pathways, elevation in glutamate concentration, and induction of the glucuronate pathway and nucleotide biosynthesis. These metabolic features reflect low GSH-elicited cellular response to chronic alcohol exposure, which is beneficial for the maintenance of hepatic redox and metabolic homeostasis. The current study indicates that fine-tuning of hepatic GSH pool may evoke metabolic reprogramming to cope with alcohol-induced cellular stress.
KW - Acetyl-CoA
KW - Alcoholic steatosis
KW - Glutamate cysteine ligase
KW - Glutathione
KW - Metabolomics
KW - Transcriptomics
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UR - http://www.scopus.com/inward/citedby.url?scp=85070278151&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2019.07.025
DO - 10.1016/j.freeradbiomed.2019.07.025
M3 - Article
C2 - 31351176
AN - SCOPUS:85070278151
SN - 0891-5849
VL - 143
SP - 127
EP - 139
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -