Postdoctoral Fellowship for Kraemer: Regulation and Function of Lipoprotein Associated Bioactive Lysophospholipid Mediators of Atherosclerosis

Elevated circulating levels of atherogenic lipoproteins predict increased risk of cardiovascular disease. Multiple lines of evidence implicate bioactive components of lipoprotein particles (such as oxidized phospholipids) as signaling molecules that provoke responses in blood and vascular cells that contribute to the development and progression of atherosclerosis. Studies from ourselves and others identify a role for the bioactive lipid mediator lysophosphatidic acid (LPA) as a proinflammatory atherogenic signal in preclinical models and clinical settings. LPA accumulates in atheromas, and mice lacking certain LPA receptors are protected from experimentally induced atherosclerosis. In humans, heritable variants that reduce expression of an enzyme (lipid phosphate phosphatase 3, LPP3) that can degrade and inactivate LPA associate with increased cardiovascular disease risk. In preliminary data I show that LPA is abundant in isolated human low density lipoprotein (LDL) and that this pool of LDL associated LPA is dramatically elevated in genetically hyperlipidemic mice fed an atherosclerosis promoting diet. Collectively, these observations provide a basis for this proposal which will combine training in preclinical research, analytical mass spectrometry and mouse models of lipoprotein metabolism and atherosclerosis to define effects of diet and hyperlipidemia on sources and circulating levels of lipoprotein associated LPA and to identify the contribution of LPA to the signaling effects of LDL on blood and vascular cells. Aim 1 will test the hypothesis that diet affects circulating pools of LPA with particular focus on LPA-associated LDL by studying genetically hyperlipidemic mice fed normal or atherosclerosis promoting diets. Levels and distribution of LPA-associated with plasma lipids and lipoproteins will be analyzed before and after diet. We will then use genetic and pharmacological methods to study the role of LPP3 and an LPA generating phospholipase, autotaxin as regulators of LDL associated LPA pools. Aim 2 will extrapolate these studies to test the hypothesis that the LPA content of LDL modulates signaling actions of relevant blood and vascular cell types. Completion of these aims will provide new insights into a plausible mechanism by which diet and genetic risk factors could interact to determine atherosclerosis risk.