以色列理工学院Eyal Gottlieb，Inbal Mor和美国路易斯安那州立大学健康科学中心Oren Rom共同合作，近期取得重要工作进展。他们研究提出，在MASLD中，通过逆转SHMT2活性的丝氨酸合成可导致甘氨酸耗竭和对乙酰氨基酚肝毒性。相关研究成果2024年1月2日在线发表于《细胞—代谢》杂志上。

据介绍，代谢功能障碍相关的脂肪变性肝病（MASLD）影响着全球三分之一的人口。了解所涉及的代谢途径可以为疾病进展和治疗提供见解。

早期脂肪变性小鼠肝脏的非靶向代谢组学发现甲基化代谢产物减少，表明单碳代谢发生了改变。肝脂肪变性小鼠的甘氨酸水平较低，甘氨酸是单碳代谢的中心成分，与临床证据一致。稳定同位素追踪表明，通过反向丝氨酸羟甲基转移酶（SHMT）从甘氨酸合成丝氨酸的增加是脂肪变性肝脏中甘氨酸减少的根本原因。

因此，在对乙酰氨基酚诱导的氧化应激下，脂肪变性肝脏中甘氨酸的有限可用性损害了谷胱甘肽的合成，增强了急性肝毒性。在患有肝脂肪变性的小鼠中补充甘氨酸或肝细胞特异性消融线粒体SHMT2亚型，通过支持谷胱甘肽的从头合成来减轻对乙酰氨基酚诱导的肝毒性。

因此，MASLD的早期代谢变化限制了甘氨酸的可用性，即使在这种疾病的可逆阶段，也会使小鼠对外源性药物敏感。

附：英文原文

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

Author: 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 Chen, Oren Rom, Inbal Mor, Eyal Gottlieb

Issue&Volume: 2024/01/02

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-thirdof the global population. Understanding the metabolic pathways involved can provideinsights into disease progression and treatment. Untargeted metabolomics of liversfrom mice with early-stage steatosis uncovered decreased methylated metabolites, suggestingaltered one-carbon metabolism. The levels of glycine, a central component of one-carbonmetabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence.Stable-isotope tracing demonstrated that increased serine synthesis from glycine viareverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreasedglycine in steatotic livers. Consequently, limited glycine availability in steatoticlivers impaired glutathione synthesis under acetaminophen-induced oxidative stress,enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablationof the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-inducedhepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycineavailability sensitize mice to xenobiotics even at the reversible stage of this disease.

DOI: 10.1016/j.cmet.2023.12.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00464-3