PPARs: Important Regulators in Metabolism and Inflammation

Abstract

The ligand-activated family of peroxisome proliferator activated receptors (PPARs) consists of three members named PPAR alpha, PPAR delta and PPAR gamma. Each PPAR subtype is characterized by a specific tissue expression pattern, partially accounting for distinct biological functions. Analogous to many other nuclear receptors, PPARs form heterodimers with the retinoid X receptor and regulate DNA transcription by binding to specific response elements present in target genes. PPAR alpha (NR1C1) is highly expressed in liver, heart, intestine, skeletal muscle, and various immune cells. Agonists for PPAR alpha include the lipid-lowering fibrate drugs as well as numerous fatty acids and eicosanoids. PPAR alpha is known to play an important role in many different metabolic processes, especially under conditions of fasting, and has proven to be an important regulator of inflammation via inhibition of gene expression. PPAR delta (NR1C2) is ubiquitously expressed but its function has mainly been studied in skin, heart, and skeletal muscle. In the past few years, it has become evident that PPAR delta is involved in numerous biological processes including lipid metabolism, wound healing and inflammation. The most studied PPAR subtype is PPAR gamma (NR1C3), which is expressed at high levels in adipose tissue, macrophages and vascular cells. PPAR gamma drives adipocyte differentiation, has important regulatory roles during fat storage and glucose metabolism, and is an important suppressor of inflammation. Importantly, it serves as the molecular target for the thiazolidionedione drugs. In this chapter we provide an overview of the major functions of the three PPAR subtypes, and focus on their role in metabolic and inflammatory processes.