Deletion of Betaine-Homocysteine S-Methyltransferase in Mice Perturbs Choline and 1-Carbon Metabolism, Resulting in Fatty Liver and Hepatocellular Carcinomas

Abstract

Betaine-homocysteine S-methyltransferase (BHMT) uses betaine to catalyze the conversion of homocysteine (Hcy) to methionine. There are common genetic polymorphisms in the BHMT gene in humans that can alter its enzymatic activity. We generated the first Bhmt Histopathological analysis revealed that Bhmt ؊/؊ mice developed hepatocellular carcinoma or carcinoma precursors. These results indicate that BHMT has an important role in Hcy, choline, and one-carbon homeostasis. A lack of Bhmt also affects susceptibility to fatty liver and hepatocellular carcinoma. We suggest that functional polymorphisms in BHMT that significantly reduce activity may have similar effects in humans.Betaine-homocysteine S-methyltransferase (BHMT) 2 is a zinc-dependent cytosolic enzyme that catalyzes the transfer of a methyl group from betaine to homocysteine (Hcy) forming dimethylglycine and methionine (Met) (Fig. 5). Humans have common single nucleotide polymorphisms in the BHMT gene that alter BHMT enzyme activity and function (1). A common BHMT single nucleotide polymorphism rs3733890 (41% of NC population has 1 variant allele, and 8% have 2 alleles (2)) was associated with increased risk for having babies with neural tube defects (3), decreased risk for developing cardiovascular disease (4), and reduced risk for breast cancer-specific mortality (5). The epidemiological evidence suggests the importance of single nucleotide polymorphisms in the gene. However, the metabolic consequences of having null mutations of the BHMT gene have not been thoroughly investigated. To directly investigate the role of BHMT in vivo, we generated and characterized mice in which the gene encoding Bhmt was deleted (Bhmt Ϫ/Ϫ ). BHMT activity is found at high levels in the liver and kidney, and low levels in the brain, lenses, and other human tissues. In rodents, high levels of BHMT activity are only found in the liver (6). Betaine, the methyl donor for BHMT, comes from either dietary sources or from oxidation of choline (an irreversible reaction) by choline dehydrogenase (CHDH). Alternatively, choline can be used to form the phospholipid phosphatidylcholine (PtdCho) or the neurotransmitter acetylcholine (7). The product of BHMT, methionine, is the precursor for S-adenosylmethionine (AdoMet), the major methyl donor for most biological methylations, including DNA and histone methylation, the conversion of glycine to methylglycine (catalyzed by glycine methyltransferase (GNMT)), and the methylation of phosphatidylethanolamine (PtdEtn) to form PtdCho (catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT)).The other substrate for BHMT is Hcy, a thiol-containing amino acid, which, when elevated in plasma, is associated with cardiovascular diseases, pregnancy complications, renal insufficiency, and cognitive impairment (8). Hcy is converted to methionine by BHMT or by methionine synthase, the latter of which uses methyltetrahydrofolate (methyl-THF) as the methyl

Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

“…We observed that Bhmt-deficient (Bhmt Ϫ/Ϫ ) mice had a lower body weight from 5 to 9 weeks of age compared with wild type littermates (2). Magnetic resonance image (MRI) analysis and dissection of adipose fat depots revealed that the reduced * This work was supported, in whole or in part, by National Institutes of body weight observed in Bhmt Ϫ/Ϫ mice was due to reduced fat depots.…”

“…Adipocytes-We previously reported that Bhmt Ϫ/Ϫ mice gained less body weight between 5 and 9 weeks of age than did their wild type littermates (p Ͻ 0.05) (2). To determine whether the reduced weight gain of Bhmt Ϫ/Ϫ mice was associated with reduced fat or lean mass, we measured body composition of these mice using MRI scan analysis.…”

“…Second, methionine, the end product of BHMT, is the precursor of S-adenosylmethionine, which is required for the synthesis of PtdCho from phosphatidylethanolamine by the enzyme phosphatidylethanolamine methyltransferase. BHMT overexpression increases PtdCho synthesis, leading to reduced hepatic lipid accumulation (3), whereas BHMT deficiency leads to fatty liver (2). Although the role of BHMT in hepatic lipid metabolism has been elucidated, there is no previous evidence that BHMT plays a role in whole body energy metabolism and adiposity.…”

“…BHMT catalyzes the formation of the amino acid methionine from homocysteine using the choline metabolite betaine as the methyl donor. BHMT deficiency leads to elevated betaine and homocysteine concentrations and reduced choline concentration (2). BHMT also influences hepatic lipid accumulation via altering phosphatidylcholine (PtdCho) concentration.…”

Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

“…SAHH dysfunction is linked to numerous pathologies such as neurological and vascular disorders, myopathy, fatty liver, cancer, renal insufficiency, and diabetic nephropathy (5)(6)(7)(8)(9)(10)(11)(12)(13). Deletion of SAHH in mice is embryonically lethal (14).…”