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.

Triiodothyronine treatment attenuates the induction of hepatic glycine N-methyltransferase by retinoic acid and elevates plasma homocysteine concentrations in rats.

Recent studies indicated that hormonal imbalances have a role in modulating the metabolism of methyl groups and homocysteine, interrelated pathways that when disrupted, are associated with a number of pathologies. Retinoic acid (RA) was shown to induce hepatic glycine N-methyltransferase (GNMT), a key regulatory protein in methyl group metabolism, and to reduce circulating homocysteine levels. Because thyroid status influences the hepatic folate-dependent one-carbon pool and retinoids can alter thyroid hormone levels, the aim of this study was to examine the interaction between retinoids and thyroid function. For hypothyroid studies, rats were administered 0.5 g/L propylthiouracil in the drinking water for 15 d, and RA [30 micromol/(kg . d)] for the final 5 d. For hyperthyroid studies, rats were treated with RA [30 micromol/(kg . d)] for 8 d and triiodothyronine [T(3); 50 microg/(100 g . d)] the last 4 d. T(3) treatment prevented the RA-mediated increase in GNMT activity. However, GNMT abundance remained elevated, indicating that GNMT regulation by T(3) in RA-treated rats may be, at least in part, at the post-translational level. In addition, T(3) treatment elevated plasma levels of homocysteine 177%, an elevation that was prevented by RA. T(3)-mediated hyperhomocysteinemia may be due to a 70% decrease in hepatic betaine-homocysteine S-methyltransferase, the enzyme that catalyzes folate-independent remethylation of homocysteine, whereas the RA-mediated stimulation of hepatic homocysteine remethylation by folate-dependent methionine synthase may contribute to lowering plasma homocysteine levels. These findings indicate that thyroid hormones, alone and in conjunction with RA, play an important role in the regulation of methyl group and homocysteine metabolism.