Faculty, Staff and Student Publications
Publication Date
1-2-2024
Journal
Cell Metabolism
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.
Keywords
Animals, Mice, Acetaminophen, Carbon, Chemical and Drug Induced Liver Injury, Fatty Liver, Glutathione, Glycine, Glycine Hydroxymethyltransferase, Serine, MASLD, glycine, acetaminophen hepatotoxicity, glutathione, xenobiotic, one carbon metabolism, SHMT
DOI
10.1016/j.cmet.2023.12.013
PMID
38171331
PMCID
PMC10777734
PubMedCentral® Posted Date
1-2-2025
PubMedCentral® Full Text Version
Author MSS
Graphical Abstract
Published Open-Access
yes
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons