Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that act as transcription factors for gene expression by binding to specific DNA sequences. They have been shown to have a role in several physiological processes including carbohydrate and lipid metabolism as well as inflammation and fibrogenesis, and represent a promising target for therapy.
The PPAR family comprises three isoforms: PPARα, PPARδ (also called PPARβ) and PPARγ, which are differentially expressed in various tissues.
PPARα is expressed ubiquitously but most highly in the liver. PPAR-α plays a critical role in the regulation of fatty acid transport and β-oxidation and triglyceride turnover, is involved in regulation of energy homeostasis and is thought to have anti-inflammatory effects through complex regulation of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and activator protein 1 (AP1) transcription factors.
PPARδ is expressed mainly in skeletal muscle and to a lesser degree in adipose tissue and liver. PPARδ contributes to the regulation of glucose and lipid metabolism and is involved in regulating mitochondrial metabolism and fatty acid β-oxidation in muscle. It is also present in Kupffer cells and HSCs, and may therefore have role in inflammation and fibrosis since HSCs as well as portal fibroblasts are the main source of hepatic myofibroblasts.
Furthermore, PPARδ is also expressed in vascular cells including endothelial cells, smooth muscle cells and macrophages, and it plays an important role in various basic vascular processes such as apoptosis, survival, angiogenesis and inflammation.
PPARγ is highly expressed in adipose tissue and plays an essential role in the regulation of adipocyte differentiation, adipogenesis and lipid metabolism; its activation induces insulin sensitisation, enhances glucose metabolism, increases triglyceride storage in adipocytes while decreasing liver steatosis in humans. In addition, it stimulates secretion of the anti-inflammatory cytokine adiponectin. PPARγ is also expressed in HSCs where It plays a key role in maintaining them inactive. Furthermore, forced expression of PPARγ has been shown to reverse activated HSCs to their quiescent state