During the past five years, transgenic mice expression high plasma levels of human apolipoprotein (apo) B have been generated using an 80-kb P1 bacteriophage clone, p158, that spans the human apo-B gene. During the analysis of those mice, a highly unexpected and provocative finding was made: that the apo-B gene was expressed by cardiac myocytes, at a level of about 4% of that found in the liver and approximately 10-15% of that found in the intestine. Heart tissue also expresses microsomal triglyceride transfer protein (MTP). Metabolic labeling studies revealed that apo-B- containing lipoproteins are secreted by heart tissue from the human apo-B transgenic mice, fresh human heart tissue obtain from cardiac transplantation operations, and heart tissue from non-transgenic mice. In this renewal application, there are two specific aims.
Aim 1 is to characterize lipoprotein secretion by the heart using in vitro techniques. Using mouse models, the temporal pattern of apo-B and MTP gene expression during heart development will be analyzed. Ultrastructural studies and metabolic labeling studies will be used to determine whether the size and density of heart lipoproteins can be modulated by lipid loading of cardiac myocytes.
Aim 2 will be to use genetically modified mice to test the hypothesis that the secretion of apo-B-containing lipoproteins is physiologically important for exporting surplus cellular lipids back into the blood stream. Tissue-specific knockout mice lacking apo-B expression in the heart will be generated and used to test the hypothesis that the absence of heart lipoprotein secretion would result in the accumulation of lipids within cardiac myocytes. Also, pharmacological and genetic experiments will be performed to determine whether the over-expression of apo-B in the heart would reduce intracellular fat accumulation in cardiac myocytes of mice that are prone to the development of fatty pathology in the heart.
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