NEW TRANSGENIC MODELS OF HYPERTRIGLYCERIDEMIA

The apolipoproteins (apo) C are major constituents of VLDL, HDL and chylomicrons. Of the three apoC's, only apoCII, the activator of lipoprotein lipase (LPL), has a clearly-established role in lipoprotein metabolism. Overexpression of all three proteins causes hypertriglyceridemia in transgenic (Tg) mice but the dose-response relationships and lipoprotein phenotypes differ. It appears increasingly likely that overproduction of C apolipoproteins, at the least apo CIII, may be at the heart of a significant fraction of hypertriglyeridemia in humans, underlining the relevance of these models. The mechanism of hyperlipidemia remains open to dispute in all the apoC-overexpressing mice. Both decreased lipolysis and decreased remnant clearance have been considered as the primary mechanism of the hyperlipidemia in each. Studies were not done in a pure inbred background and few direct comparisons have been performed. It is unclear to what extent differences in descriptions of these models reflect the genetic variability of the strain background and variation in experimental technique. In Aim 1, we propose to perform a characterization of the metabolic effects of the apoC's using Tg mouse models. A description of the lipoprotein phenotype and a variety of kinetic and in vitro studies will be performed. Studies will be performed in an inbred atherosclerosis-prone strain, C57BL/6. Study of the atherogenicity of the different hypertriglyceridemic phenotypes produced by apoC- overexpression may shed light on the nature of atherogenic dyslipidemia as well as the plausibility of the C apolipoproteins as candidate genes in this process. In Aim 2, we will determine the effects of the transgenes on atherosclerosis using a quantitative assay. In Aim3, we will study recently-developed mice that produce only apoB48 and mice that produce only apoB100, both produced via gene targeting. Our data, and that of others, suggests that apoCIII has a greater effect on the clearance of apoB48 lipoproteins and apoCI has greater effects on the apoB100 particles. To test this, ApoCI, apoCII and apoCIII Tg mice will be crossed with the gene-targeted mice and the effects on lipoprotein metabolism will be assessed.