Peroxisome proliferator-activated receptor family and related metabolic nuclear receptors (PPAR family) (PPAR family)

The Peroxisome Proliferator-Activated Receptor (PPAR) family and related metabolic nuclear receptors, such as the Farnesoid X Receptor (FXR) and Liver X Receptor (LXR), are ligand-activated transcription factors that serve as essential sensors for metabolic flux [2, 7]. These receptors regulate systemic energy homeostasis by controlling the expression of genes involved in lipid metabolism, glucose transport, and bile acid synthesis [4, 11]. PPARα is primarily involved in fatty acid oxidation in the liver and heart, while PPARγ is the master regulator of adipogenesis and insulin sensitivity in peripheral tissues [9, 12]. Related receptors like FXR and LXR manage bile acid levels and cholesterol transport, respectively, often working in concert with PPARs through heterodimerization with the Retinoid X Receptor (RXR) [8, 10]. Dysregulation of these nuclear receptor pathways is a hallmark of metabolic syndrome, type 2 diabetes, and non-alcoholic steatohepatitis (NASH) [4, 6]. Consequently, they are major therapeutic targets; fibrates and thiazolidinediones are established treatments for dyslipidemia and diabetes, while newer selective and multi-receptor agonists are being developed to treat chronic liver diseases and complex metabolic disorders [12, 13]. However, therapeutic use is often limited by side effects such as weight gain, fluid retention, and pruritus, necessitating the development of more selective modulators [4, 8].

Other names

NR1C subfamilyNR1H subfamilyNuclear receptor subfamily 1 group CNuclear receptor subfamily 1 group HGlitazone receptorsFibrate receptorsBile acid receptorsOxysterol receptors

Agonism of specific nuclear receptor isoforms (PPARα, PPARβ/δ, PPARγ, FXR, or LXR) leads to heterodimerization with the Retinoid X Receptor (RXR). These complexes bind to specific response elements in the promoter regions of target genes, recruiting co-activators and initiating the transcription of genes involved in lipid oxidation, glucose transport, and bile acid homeostasis [8, 10, 12].