The major lipoprotein risk factor for coronary heart disease in the United States today is low HDL cholesterol, usually accompanied by high triglycerides. The investigators intend to use our expertise in the molecular biology of the apolipoprotein genes and lipoprotein metabolism to create induced mutant mice and use them to study how apolipoprotein genes regulate HDL and triglyceride levels. The investigators will also carefully examine the implications of altered levels for atherosclerosis susceptibility. The current work will focus on the apo A-I, apo A-II and apo CIII genes. The investigators propose to use the apo A-I knockout mouse to study the effect of apo A-I on HDL metabolism and atherosclerosis susceptibility. In these studies the investigator will determine whether low HDL levels are an independent modifier of atherosclerosis and elucidate the mechanism. The investigator will examine possible overlapping functions of apo A-I and apo A-IV with regard to reverse cholesterol transport and atherosclerosis susceptibility. Finally, the investigator will study the apo A-I adrenal cell interaction to determine if an HDL/apo A-I receptor is involved and, if so, clone the receptor. The investigator will also generate and characterize apo A-II knockout mice and use these to define the functional role of apo A-II in vivo. The investigators will test whether apo A-II inhibits HL activity, inhibits remnant clearance, regulates FFA levels, and influences atherosclerosis susceptibility. The explorations of the apo CIII gene expression-hypertriglyceridemia relationship will continue. The investigators will use apo CIII knockout mice to test whether hypertriglyceridemia associated with insulin deficiency or resistance is mediated by apo CIII gene expression. The investigators will determine whether apo CIII promoter genetic variation controls insulin regulation of apo CIII gene expression and triglyceride levels in vivo. The investigators will examine the influence of the apo CIII gene Sstl 3'UTR polymorphism on apo CIII mRNA stability and determine possible interactions between the apo CIII promoter polymorphisms and the Sstl 3' UTR polymorphism.
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