Peroxisome proliferator-activated receptor (PPAR) isoforms in coronary heart disease

Abstract

Coronary heart disease (CHD) is a complex disease resulted from interaction of numerous genetic and environmental factors. It is expected that understanding of complex interaction between genetic factors and environmental factors would contribute to clarifying the pathogenesis of CHD, prevention of diseases by modifying of genetic material and advancing of treatment of diseases. Hyperlipidemia is the primary risk factor for atherosclerosis and CHD. In past years, extensive studies were done on cholesterol levels and the genes that coordinate the effects of cholesterol receptor and transporters. The members of nuclear receptor super family, especially the peroxisome proliferator-activated receptors (PPAR) are the most important regulators in this course. PPARs are potential transcriptional factors that regulate fatty acid and carbohydrate metabolism and are dietary lipid sensors. Three subtypes (alfa, beta/delta, gama) are encoded by separate genes and expressed in different tissues. PPAR alpha regulates the expression of genes related to lipid metabolism, monocyte accumulation and adhesion, and formation of foam cell. In animal model of obesity and diabetes mellitus, PPAR beta/delta is suggested to be a suitable target in hyperlipidemia, increasing HDL-cholesterol and reducing adipose fatty acid storage, triglyceride, fasting insulin levels, and small and dense LDL. Furthermore, it was discovered that PPAR beta/delta activates the oxidation of fatty acid by increasing the expression of genes involved in utilization of fatty acid in heart and skeletal muscles and changing skeletal type fibril from glycolytic to oxidative state. PPAR gamma takes part in the regulation of many target genes expression which involved in adipocyte differentiation, lipid metabolism, and glucose homeostasis. PPAR gamma also appears to possess an immune suppressive function, which could favor an anti-atherosclerotic effect. All above findings together have suggested that PPAR would be a promising candidate gene for obesity and diabetes and subsequently for CHD.