TY - JOUR
T1 - Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD
AU - Ghrayeb, Alia
AU - Finney, Alexandra C.
AU - Agranovich, Bella
AU - Peled, Daniel
AU - Anand, Sumit Kumar
AU - McKinney, M. Peyton
AU - Sarji, Mahasen
AU - Yang, Dongshan
AU - Weissman, Natan
AU - Drucker, Shani
AU - Fernandes, Sara Isabel
AU - Fernández-García, Jonatan
AU - Mahan, Kyle
AU - Abassi, Zaid
AU - Tan, Lin
AU - Lorenzi, Philip L.
AU - Traylor, James
AU - Zhang, Jifeng
AU - Abramovich, Ifat
AU - Chen, Y. Eugene
AU - Rom, Oren
AU - Mor, Inbal
AU - Gottlieb, Eyal
N1 - Copyright © 2023 Elsevier Inc. All rights reserved.
PY - 2024/1/2
Y1 - 2024/1/2
N2 - Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
KW - MASLD
KW - SHMT
KW - acetaminophen hepatotoxicity
KW - glutathione
KW - glycine
KW - one-carbon metabolism
KW - xenobiotic
KW - Acetaminophen/toxicity
KW - Serine/metabolism
KW - Carbon
KW - Glutathione/metabolism
KW - Fatty Liver
KW - Glycine Hydroxymethyltransferase/metabolism
KW - Glycine/metabolism
KW - Animals
KW - Mice
KW - Chemical and Drug Induced Liver Injury
UR - http://www.scopus.com/inward/record.url?scp=85181766045&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2023.12.013
DO - 10.1016/j.cmet.2023.12.013
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C2 - 38171331
AN - SCOPUS:85181766045
SN - 1550-4131
VL - 36
SP - 116-129.e7
JO - Cell Metabolism
JF - Cell Metabolism
IS - 1
ER -