Peroxisome proliferator-activated receptors (PPARs) are a group of
nuclear receptors whose
ligands include
fatty acids,
eicosanoids and the
fibrate class of drugs. In humans,
fibrates are used to treat
dyslipidemias. In rodents,
fibrates cause peroxisome proliferation, a change that might explain the observed
hepatomegaly. In this study, rats were treated with multiple dose levels of six
fibric acid analogs (including
fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular
hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity.
RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular
hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal beta-oxidation, increased
fatty acid transport, increased hepatic uptake of
LDL-cholesterol, decreased hepatic uptake of
glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of
fibrate drugs, including decreased serum
triglycerides, decreased serum
LDL-cholesterol and increased serum
HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that
hepatomegaly is due to
PPARalpha activation, although signaling through other receptors (e.g.
PPARgamma, RXR) or through non-receptor pathways cannot be excluded.