Activation of PPARδ alters lipid metabolism in db/db mice

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPAR alpha and PPAR gamma, relatively little is known about the most widely expressed PPAR subtype, PPAR delta. Here we show that treatment of insulin resistant db/db mice with the PPAR delta agonist L-165041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated,vith high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data,were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity,vas reduced following treatment with the PPAR delta ligand, but was increased by a PPAR gamma agonist. These data suggest both that PPAR delta is involved in the regulation of cholesterol metabolism in db/db mice and that PPAR delta ligands could potentially have therapeutic value. (C) 2000 Federation of European Biochemical Societies.