The metabolic consequences of mouse betaine homocysteine S-methyltransferase deficiency
Abstract
Betaine homocysteine S-methyltransferase (BHMT, EC 2.1.1.5) catalyzes the conversion of homocysteine to methionine. Homocysteine is a potentially harmful amino acid. Its elevation is often associated with cardiovascular disease, birth defect, renal insufficiency, and age-related cognitive impairment in humans. Humans have common single nucleotide polymorphisms (SNPs) in the BHMT gene that can alter its enzyme activity and function. Elucidation of the metabolic consequences of BHMT deficiency is critical to the understanding of the relationship between BHMT mutations and diseases. To directly investigate the role of BHMT in vivo, we generated and characterized the mice with the gene encoding Bhmt deleted (Bhmt-/-). This dissertation describes two separate projects. The first project examines the roles of BHMT in one-carbon metabolism and the development of hepatic steatosis and hepatocellular carcinoma. The second project examines the role of BHMT in energy metabolism. In the first project, we generated and characterized the Bhmt-/- mouse. We found that deletion of Bhmt resulted in elevated homocysteine concentrations, in reduced methylation potential, and in profound alterations of choline metabolites in various tissues. Bhmt-/- mice developed fatty liver at five weeks of age due to reduced phosphatidylcholine concentration. Phosphatidylcholine is required for the synthesis of lipoproteins, which carry lipids from the liver to circulation. By one year of age, 64% of Bhmt-/-…
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