Relationship of Apo B and BHMT: Nutrition and Physiology

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DESCRIPTION (provided by applicant): Apolipoprotein B (Apo B) is important in lipid transport in lipoproteins (LP), and as a factor associated with risk of macrovascular disease complications (heart attacks, strokes). B48 and B100 are forms of apo B that, in humans, represent intestinal and hepatic products of translation that are derived from edited and unedited apo B mRNA transcribed from a single copy gene. In McArdle RH-7777 (McA) cells, the restoration of betaine homocysteine S-methyltransferase (BHMT) expression through transfection is positively correlated with apo B mRNA abundance and increases in B48 and B100 secretion. BHMT catalyzes transfer of a methyl group from betaine to homocysteine to form methionine. BHMT and methionine synthase contribute equally to methionine formation from homocysteine in rat liver. BHMT can be induced in a variety of nutritional states in vivo. Aim 1 is to establish the physiological relationship between BHMT and apo B. Using dietary conditions that alter BHMT expression, changes in apo B mRNA will be evaluated in rats. Aim 2 will evaluate the impact of apo B mRNA and BHMT pathways on hepatic lipoprotein metabolism in rat hepatocytes (RH) and BHMT-transfected McA cells. Hepatic biogenesis of B100 and B48 will be studied including apo B translation, intracellular LP assembly, apo B degradation, and LP secretion. In order to assess mechanisms of apo B mRNA abundance changes, apo B mRNA stability and apo B gene transcription will be documented. BHMT may function in hepatic lipid metabolism directly, and experiments will test whether BHMT mediates methyl transfer from betaine to phosphatidylethanolamine in the formation of phosphatidyicholme necessary in apo B-Lp secretion. The overall research goal is to understand and characterize BHMT metabolic pathways and potential relationships to apo B biogenesis. A potential link of two pathways whose products or intermediates are associated with increased cardiovascular disease risk could be established.