Journal of Lipid Research (Jul 1999)
Rosiglitazone (BRL49653), a PPARγ-selective agonist, causes peroxisome proliferator-like liver effects in obese mice
Abstract
The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated nuclear receptors that regulate genes involved in lipid metabolism and homeostasis. PPARα is preferentially expressed in liver and PPARγ preferentially in adipose tissue. Activation of PPARα leads to peroxisome proliferation and increased β-oxidation of fatty acids in rodents. PPARγ-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both PPAR receptors are believed to be functional targets for treatment of hyperlipidemia in man. We have treated obese diabetic mice (ob/ob), which have highly elevated levels of plasma triglycerides, glucose and insulin, for 1 week with WY14,643 (180 μmol/kg/day), a selective PPARα agonist, or rosiglitazone (BRL49653; 2.5 μmol/kg/day), a selective PPARγ agonist. The doses used produce a similar therapeutic effect in both treatment groups (lowering of triglycerides and glucose). High resolution two-dimensional gel electrophoresis of livers showed that WY14,643 and rosiglitazone both produced changes in expression pattern of many proteins involved in peroxisomal fatty acid β-oxidation. However, similar experiments performed in lean mice showed significant up-regulation of these proteins only with WY14,643 treatment. Furthermore, the proteins up-regulated by the drugs in obese mice had a higher basal expression in obese controls compared to the lean littermates. Liver PPARγ mRNA levels were determined and we observed that PPARγ2 mRNA levels were elevated in obese mice compared to lean littermates. As PPARα and PPARγ recognize similar DNA response elements, it is likely that the effects of rosiglitazone on PPARα responsive genes in livers of the ob/ob mice are mediated by PPARγ2.—Edvardsson, U., M. Bergström, M. Alexandersson, K. Bamberg, B. Ljung, and B. Dahllöf. Rosiglitazone (BRL49653), a PPARγ-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. J. Lipid Res. 1999. 40: 1177–1184.
