Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovascular disease risk is caused by environmental and heritable factors. The broad goal of our research is to understand how these factors interact to determine overall disease risk. In current funding period of this award we studied how heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate with heritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of the gene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results in accelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an “atherosclerosis suppressor” gene and that heritable variants that decrease expression of the gene promote heart disease risk. LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipid mediators. One of these LPP3 substrates, lysophosphatidic acid (LPA) acts on multiple blood and vascular cells to promote inflammation and cardiovascular disease progression. In mice, genetic or pharmacological targeting of LPA modulates atherosclerosis. In our mouse studies, LPP3 deficiency was associated with increased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesis that dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 on cardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. In preliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. This diet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestine from dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low density lipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is a secreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources of circulating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also an intermediate in the synthesis of triglycerides by the intestine and liver so, since this process is coupled to the generation of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo. The first aim of this proposal will test these competing hypotheses directly by using stable isotope tracers and mass spectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studies will allow us to use genetic and pharmacological approaches to selectively manipulate ATX, LPP3 and the formation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signaling responses in blood and vascular cell types that underlie the initiation and progression of ca...