Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice

The peroxisome proliferator-activated receptor-alpha (PPAR alpha) controls gene expression in response to a diverse class of compounds collectively referred to as peroxisome proliferators. Whereas most known peroxisome proliferators are of exogenous origin and include hypolipidemic drugs and other industrial chemicals, several endogenous PPAR alpha activators have been identified such as fatty acids and steroids, The latter finding and the fact that PPAR alpha modulates target genes encoding enzymes involved in lipid metabolism suggest a role for PPAR alpha in lipid metabolism, This was investigated in the PPAR alpha-deficient mouse model, Basal levels of total serum cholesterol, high density lipoprotein cholesterol, hepatic apolipoprotein A-I mRNA, and serum apolipoprotein A-I in PPAR alpha-deficient mice are significantly higher compared with wild type controls, Treatment with the fibrate Wy 14,643 decreased apoA-I serum levels and hepatic mRNA levels in wild-type mice, whereas no effect was detected in the PPAR alpha-deficient mice, Administration of the fibrate Wy 14,643 to wild-type mice results in marked depression of hepatic apolipoprotein C-III mRNA and serum triglycerides compared with un treated controls, In contrast, PPAR alpha-deficient mice were unaffected by Wy 14,643 treatment, These studies demonstrate that PPAR alpha modulates basal levels of serum cholesterol, in particular high density lipoprotein cholesterol, and establish that fibrate induced modulation in hepatic apolipoprotein A-I, C-III mRNA, and serum triglycerides observed in wild-type mice is mediated by PPAR alpha.