PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice

PPAR alpha is a ligand-dependent transcription factor expressed at high lev els in the liver. Its activation by the drug gemfibrozil reduces clinical e vents in humans with established atherosclerosis, but the underlying mechan isms are incompletely defined. To clarify the role of PPAR alpha in vascula r disease, we crossed PPAR alpha -null mice with apoE-null mice to determin e if the genetic absence of PPAR alpha affects vascular disease in a robust atherosclerosis model. On a high-fat diet, concentrations of atherogenic l ipoproteins were higher in PPAR alpha (-/-)apoE(-/-) than in PPAR alpha (+/ +)apoE(-/-) mice, due to increased VLDL production. However, en face athero sclerotic lesion areas at the aortic arch, thoracic aorta, and abdominal ao rta were less in PPAR alpha -null animals of both sexes after 6 and 10 week s of high-fat feeding. Despite gaining as much or more weight than their PP AR alpha (+/+)apoE(-/-) littermates, PPAR alpha (-/-)apoE(-/-)mice had lowe r fasting levels of glucose and insulin. PPAR alpha -null animals had great er suppression of endogenous glucose production in hyperinsulinemic clamp e xperiments, 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-induce d insulin resistance and atherosclerosis.