Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders
Figure 2
Signaling pathways activating PPAR and regulating the biological effects of
PPAR in different organs. PPAR activity can be regulated by the direct binding
of small lipophilic ligands. Ligand-unbound PPAR in the cytosol is associated
with chaperons, and the association changes the conformation of PPAR that
allows for high-affinity binding to the ligand. Ligand-bound PPAR forms a heterodimer
with RXR, and the PPAR-RXR heterodimer constructs the transcriptional machinery
through the recruitment of coregulators. The transcriptional machinery
regulates gene expression by binding to specific DNA sequence elements, termed
PPAR response elements (PPRE). PPARα is strongly
expressed in the liver, heart, and blood vessels, and regulates the expressions
of genes related to lipid metabolism and inflammation control. PPARγ exerts its effects on insulin sensitivity and
glucose homeostasis in adipocytes and skeletal muscles. PPARδ is expressed ubiquitously, and controls the expressions
of genes that are involved in glucose and lipid metabolism. FA: fatty acid; HDL:
high-density lipoprotein; VDL: very low-density lipoprotein; ABCA1: ATP-binding
cassette transporter A1; UCP: uncoupling protein; TG: triglyceride.