Abstract 396: Diet-derived Lysophosphatidic Acid and Obesity-associated Cardiovascular Disease Risk

Abstract

Diet-dependent obesity is a risk factor for coronary artery disease and a powerful risk factor for some cancers particularly in women. One mechanism that has been proposed to link diet-dependent obesity to disease is that diets high in fats and lipids promote the formation of bioactive lipid metabolites that increase disease risk. Lysophosphatidic acid (LPA) is a family of bioactive lysophospholipids that elicit broadly mitogenic and proinflammatory responses in multiple cell types, primarily through actions at cell surface G-protein coupled receptors. LPA promotes vascular smooth muscle cell differentiation and migration, decreases vascular barrier endothelial function, activates platelets and myeloid cells all of which could contribute to the development of atherosclerosis. In mice, genetic and pharmacological targeting of LPA receptors inhibits atherosclerosis. We conducted studies to investigate the impact of fasting and high fat feeding on circulating levels, metabolic sources and distribution of plasma LPA in both humans and mice. After overnight fasting, blood was drawn from human volunteers to obtain baseline LPA levels before being given a drink supplemented with fats to provide approximately 50% of daily energy requirement. Blood was subsequently drawn at intervals to prepare plasma. In mice, after overnight fasting, the animals were gavaged with olive oil either with or without a tracer phosphatidylcholine. These studies were extended to mice with genetically induced hyperlipidemia fed models of diet. Changes in plasma LPA levels were measured by using HPLC ESI multistage mass spectrometry. We found that plasma LPA levels in mice and humans are acutely sensitive to fasting and high fat feeding. In mice plasma LPA levels are dramatically increased by a combination of feeding a high fat atherogenic diet and genetic induction of hyperlipidemia by inactivation of the LDLr or apoE genes. In addition, in mice, plasma LPA can be formed from dietary phosphatidylcholine. These results provide support for the concept that high fat atherogenic diets promote the formation of circulating LPA and have led to development and characterization of mouse models that can be used to define the role of LPA in obesity in other disease processes including cancer.