Bezafibrate is a dual ligand for PPARα and PPARβ: Studies using null mice

Bezafibrate is a known activator of peroxisome proliferator-activated receptors (PPARs) that can activate both PPARα and PPARβ. To determine the role(s) of these receptors in mediating the biological effects of this chemical, the effect of bezafibrate was examined in PPARα-null and PPARβ-null mice. Wild-type, PPARα-null, or PPARβ-null mice were fed either a control diet or one containing 0.5% bezafibrate for 10 days. Bezafibrate feeding caused a significant increase in liver weight in wild-type and PPARβ-null mice compared to controls, while liver weight was unchanged in bezafibrate-fed PPARα-null mice. Gonadal adipose stores were significantly smaller in wild-type and PPARβ-null mice fed bezafibrate than in controls, and this effect was not found in similarly fed PPARα-null mice. Analysis of liver, white adipose tissue, and intestinal mRNAs showed that bezafibrate caused similar changes of mRNAs encoding lipid metabolizing enzymes in wild-type and PPARβ-null mice compared to controls. Interestingly, in PPARα-null mice, bezafibrate also induced several mRNAs previously thought to be solely controlled by PPARα, showing that the effects of this drug are not exclusively modulated by this PPAR isoform. Western blot analysis of liver protein was consistent with changes in mRNA expression showing that the alterations in mRNA expression correlate with protein expression in this tissue. Results from these studies demonstrate that the effect of bezafibrate is mediated in large part by PPARα, although some changes in gene expression are dependent on PPARβ. In contrast to other PPARα ligands such as WY-14,643, induction of some target genes by bezafibrate can also be modulated in the absence of a functional PPARα.