PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice.
PPARalpha 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 PPARalpha in vascular disease, we crossed PPARalpha-null mice with apoE-null mice to determine if the genetic absence of PPARalpha affects vascular disease in a robust atherosclerosis model. On a high-fat diet, concentrations of atherogenic lipoproteins were higher in PPARalpha(-/-)apoE(-/-) than in PPARalpha(+/+)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 PPARalpha-null animals of both sexes after 6 and 10 weeks of high-fat feeding. Despite gaining as much or more weight than their PPARalpha(+/+)apoE(-/-) littermates, PPARalpha(-/-)apoE(-/-) mice had lower fasting levels of glucose and insulin. PPARalpha-null animals had greater suppression of endogenous glucose production in hyperinsulinemic clamp experiments, reflecting less insulin resistance in the absence of PPARalpha. PPARalpha(-/-)apoE(-/-) mice also had lower blood pressures than their PPARalpha(+/+)apoE(-/-) littermates after high-fat feeding. These results suggest that PPARalpha may participate in the pathogenesis of diet-induced insulin resistance and atherosclerosis.
Tordjman
K
K
Department of Medicine and the Center for Cardiovascular Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Bernal-Mizrachi
C
C
Zemany
L
L
Weng
S
S
Feng
C
C
Zhang
F
F
Leone
T C
TC
Coleman
T
T
Kelly
D P
DP
Semenkovich
C F
CF
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D001794:Blood Pressure; D018955:CD36 Antigens / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D008071:Lipoprotein Lipase / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011743:Pyrimidines / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D001057:Apolipoproteins E; D018955:CD36 Antigens; D018932:Chemokine CCL2; D004041:Dietary Fats; D008074:Lipoproteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D008071:Lipoprotein Lipase; D005947:Glucose