The metabolic consequences of mouse betaine homocysteine S-methyltransferase deficiency Public Deposited

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  • March 21, 2019
Creator
  • Teng, Ya-Wen
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
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-/- mice had visible hepatic tumors. Histopathological analysis revealed that Bhmt-/- mice developed hepatocellular carcinoma or carcinoma precursors. We observed that Bhmt-/- mice had reduced body weight from five to nine weeks of age. This observation led us to investigate the potential role of BHMT in energy metabolism. We found that the reduced body weight in Bhmt-/- mice was due to reduced fat mass. Bhmt-/- mice had smaller adipocytes, better glucose tolerance, and enhanced insulin sensitivity. Several factors contributed to the reduced adiposity phenotype observed in Bhmt-/- mice; these included increased energy expenditure, reduced mobilization of lipid from the liver to adipose tissue, decreased lipid synthesis within adipocytes, and enhanced whole-body glucose oxidation. This dissertation provides novel findings that BHMT plays critical roles in hepatocellular carcinoma development and energy metabolism.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition (Biochemistry) of School of Public Health."
Advisor
  • Zeisel, Steven H.
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
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