An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity
An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity
复制标题
DOI：
10.1101/gr.097212.109
复制
发表时间：
2010-01-01
期刊：
影响因子：
7
通讯作者：
Peltz, Gary
中科院分区：
文献类型：
--
作者：
Liu, Hong-Hsing;Lu, Peng;Peltz, Gary
对乙酰氨基酚引起的肝毒性是急性肝衰竭和肝移植的最常见诱因，但当代医学实践主要集中在引起肝损伤后的患者管理上。使用多个近交系小鼠品系进行综合遗传、转录和基于二维 NMR 的代谢组学分析，以及对这些数据的基于知识的过滤，确定甜菜碱-同型半胱氨酸甲基转移酶 2 (Bhmt2) 是一种饮食依赖性遗传因子，影响小鼠对对乙酰氨基酚诱导的肝毒性的易感性。通过影响蛋氨酸和谷胱甘肽的生物合成，Bhmt2 可以利用其底物（S-甲基蛋氨酸 [SMM]）来提供针对对乙酰氨基酚诱导的体内损伤的保护。由于SMM仅在植物中合成，Bhmt2以依赖饮食的方式发挥其有益作用。 Bhmt2 和受影响的生物合成途径的鉴定表明，小鼠综合基因组分析的新方法如何为重大公共卫生问题提供独特且临床适用的方法。
Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.