Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD

Alia Ghrayeb, Alexandra C. Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M. Peyton McKinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L. Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y. Eugene ChenOren Rom, Inbal Mor, Eyal Gottlieb

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)116-129.e7
JournalCell Metabolism
Volume36
Issue number1
DOIs
StatePublished - 2 Jan 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • MASLD
  • SHMT
  • acetaminophen hepatotoxicity
  • glutathione
  • glycine
  • one-carbon metabolism
  • xenobiotic

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology

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