An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity

Hong Hsing Liu, Peng Lu, Yingying Guo, Erin Farrell, Xun Zhang, Ming Zheng, Betty Bosano, Zhaomei Zhang, John Allard, Guochun Liao, Siyu Fu, Jinzhi Chen, Kimberly Dolim, Ayako Kuroda, Jonathan Usuka, Janet Cheng, William Tao, Kevin Welch, Yanzhou Liu, Joseph PeaseSteve A. De Keczer, Mohammad Masjedizadeh, Jing Shan Hu, Paul Weller, Tim Garrow, Gary Peltz

Research output: Contribution to journalArticle

Abstract

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 methyl-transferase 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-methyl-methionine [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.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalGenome Research
Volume20
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Liu, H. H., Lu, P., Guo, Y., Farrell, E., Zhang, X., Zheng, M., Bosano, B., Zhang, Z., Allard, J., Liao, G., Fu, S., Chen, J., Dolim, K., Kuroda, A., Usuka, J., Cheng, J., Tao, W., Welch, K., Liu, Y., ... Peltz, G. (2010). An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity. Genome Research, 20(1), 28-35. https://doi.org/10.1101/gr.097212.109