UC San Diego

Nuclear hormone receptors are a model for ligand activated transcription. A subfamily of three nuclear receptors, the peroxisome proliferators-activated receptors, binds fatty acids to regulate a variety of biological processes. One of these, PPAR delta, has a broad and even tissue distribution providing few clues as to its function. Recently, a high affinity synthetic ligand to this receptor has greatly facilitated the study of gene regulation by this receptor. One of the hallmarks of PPAR delta activation is an increase in serum high-density lipoprotein cholesterol levels. Because low HDLc is a hallmark of the metabolic syndrome and a significant risk factor for cardiovascular disease we attempted to discover the mechanism by which ligand activation of PPAR delta raises HDLc in mice. Surprisingly we found that PPAR delta is able to regulate the main protein component of HDL, apolipoprotein AI, in adipose tissue. Amazingly, adipose tissue transplantation of AZIP/F1 or PPAR delta knockout animals was able to rescue the effect of ligand. Recent studies have highlighted the role of PPAR alpha in oxidative metabolism. To study the effect of PPAR alpha activation in a state of increased oxidative metabolism we utilized a regimen of caloric restriction. Paradoxically PPAR alpha and PPAR alpha ligand administration during caloric restriction decreased weight loss. Analysis of gene expression revealed that activation of the fatty acid synthesis pathway in liver could be responsible for this phenotype