Mechanisms For PPARdelta Agonist-Induced Elevation of HDL in Non-Human Primates

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Reduction of LDL-cholesterol through the use of statins has been shown to significantly decrease the rate of mortality and morbidity caused by coronary heart disease (CHD). Nevertheless, CHD remains the leading cause of death for men and women in the United States. One reason for the persistence of CHD may be the lack of therapies that increase HDL-cholesterol (HDL-C). It is well established that HDL-C concentration is a strong, independent, inversely related risk factor for CHD. Because of data indicating that a 1 mg/dl increase in HDL-C decreases CHD risk by 2-3%, many pharmaceutical companies are attempting to develop therapies that will effectively elevate HDL-C levels. One class of compounds that may have great therapeutic potential are PPAR6 agonists, which in non-human primates can elevate HDL-C by 43-79% and apoA-l, the major apolipoprotein of HDL, by 43%. In this application, we propose to define the mechanisms by which PPAR6 agonists induce HDL-C elevation in non-human primates. For the mentored research phase, we will determine whether PPAR5 agonists increase HDL-C by: 1) altering HDL production or catabolism; 2) changing the activity of plasma lipases, lipid transfer proteins, and LCAT; 3) modulating the mRNA and protein expression of genes involved in HDL metabolism. For the independent research phase, we propose to determine whether PPAR6 agonists elevate HDL-C in monkeys that have been treated with antisense oligonucleotides (ASOs) that suppress hepatic expression of PPAR6. We feel confidant that these studies will provide insights for the development of more-potent PPAR6 agonists or other therapies that effectively increase HDL-C, which in turn could prevent CHD in hundreds of thousands of people each year in the United States and around the world. Scientific data indicates that increasing HDL cholesterol may decrease the risk of heart disease, the leading cause of death for men and women in the United States. We proposeto determine the mechanisms by which a new class of drugs, known as PPAR delta agonists, increase HDL-cholesterol in monkeys. Because of the high degree of similarity between the bodies of humans and monkeys, we feel confidant that these studies will provide insights for the development of therapies that could increase HDL and prevent the deaths of hundreds of thousands of people each year from heart disease.