PPAR control of metabolism and cardiovascular functions

Abstract

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases. Novel peroxisome proliferator-activated receptor (PPAR) agonists are providing new opportunities in the management of metabolic and cardiovascular diseases. In this Review, Staels and colleagues discuss the physiological regulation and actions of the PPAR family and their modulation of the atherogenic lipid profile, atherosclerosis and cardiac remodelling. Peroxisome proliferator-activated receptors (PPARs) are fatty acid sensors that regulate whole-body metabolism. Activation of PPARγ (for example, by glitazones) improves the management of diabetes mellitus by increasing insulin sensitivity. Activation of PPARα (for example, by fibrates) normalizes atherogenic dyslipidaemia, thereby lowering the risk of cardiovascular disease. PPARs are expressed in the heart, where they modulate lipid and glucose metabolism. Failing or stressed hearts switch from the preferential use of fatty acids as energy substrates to glucose oxidation, with repression of the PPARα and PPARδ pathways. Rescuing PPARδ or both PPARα and PPARδ signalling, particularly in early stages of cardiac remodelling, might be a promising therapeutic strategy for heart failure. Peroxisome proliferator-activated receptors (PPARs) are fatty acid sensors that regulate whole-body metabolism. Activation of PPARγ (for example, by glitazones) improves the management of diabetes mellitus by increasing insulin sensitivity. Activation of PPARα (for example, by fibrates) normalizes atherogenic dyslipidaemia, thereby lowering the risk of cardiovascular disease. PPARs are expressed in the heart, where they modulate lipid and glucose metabolism. Failing or stressed hearts switch from the preferential use of fatty acids as energy substrates to glucose oxidation, with repression of the PPARα and PPARδ pathways. Rescuing PPARδ or both PPARα and PPARδ signalling, particularly in early stages of cardiac remodelling, might be a promising therapeutic strategy for heart failure.