An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity.
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.
Liu
Hong-Hsing
HH
Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, California 94304, USA. honghsing.liu@gmail.com
Lu
Peng
P
Guo
Yingying
Y
Farrell
Erin
E
Zhang
Xun
X
Zheng
Ming
M
Bosano
Betty
B
Zhang
Zhaomei
Z
Allard
John
J
Liao
Guochun
G
Fu
Siyu
S
Chen
Jinzhi
J
Dolim
Kimberly
K
Kuroda
Ayako
A
Usuka
Jonathan
J
Cheng
Janet
J
Tao
William
W
Welch
Kevin
K
Liu
Yanzhou
Y
Pease
Joseph
J
de Keczer
Steve A
SA
Masjedizadeh
Mohammad
M
Hu
Jing-Shan
JS
Weller
Paul
P
Garrow
Tim
T
Peltz
Gary
G
D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D004032:Diet; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D014814:Vitamin U / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D014814:Vitamin U; D000082:Acetaminophen; D050940:Betaine-Homocysteine S-Methyltransferase