PPARα deficiency reduces insulin resistance and atherosclerosis in apoE-null mice

PPAR alpha is a ligand-dependent transcription factor expressed at high levels in the liver. Its activation by the drug gemfibrozil reduces clinical events in humans with established atherosclerosis, but the underlying mechanisms are incompletely defined. To clarify the role of PPAR alpha in vascular disease, we crossed PPAR alpha -null mice with apoE-null mice to determine if the genetic absence of PPAR alpha affects vascular disease in a robust atherosclerosis model. On a high-fat diet, concentrations of atherogenic lipoproteins were higher in PPAR alpha (-/-)apoE(-/-) than in PPAR alpha (+/+)apoE(-/-) mice, due to increased VLDL production. However, en face atherosclerotic lesion areas at the aortic arch, thoracic aorta, and abdominal aorta were less in PPAR alpha -null animals of both sexes after 6 and 10 weeks of high-fat feeding. Despite gaining as much or more weight than their PPAR alpha (+/+)apoE(-/-) littermates, PPAR alpha (-/-)apoE(-/-)mice had lower fasting levels of glucose and insulin. PPAR alpha -null animals had greater suppression of endogenous glucose production in hyperinsulinemic clamp experiments, reflecting less insulin resistance in the absence of PPAR alpha, PPAR alpha (-/-)apoE(-/-) mice also had lower blood pressures than their PPAR alpha (+/+)apoE(-/-) littermates after high-fat feeding. These results suggest that PPAR alpha may participate in the pathogenesis of diet-induced insulin resistance and atherosclerosis.