Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha

Dietary polyunsaturated fatty acids (PUFA) induce hepatic peroxisomal and microsomal fatty acid oxidation and suppress lipogenic gene expression. The peroxisome proliferator-activated receptor alpha (PPAR alpha) has been implicated as a mediator of fatty acid effects on gene transcription. This report uses the PPAR alpha-deficient mouse to examine the role of PPAR alpha in the PUFA regulation of mRNAs encoding hepatic lipogenic (fatty acid synthase (FAS) and the 514 protein (514)), microsomal (cytochrome P450 4A2 (CYP4A2)), and peroxisomal (acyl-CoA oxidase (AOX)) enzymes, PUFA ingestion induced mRNA(AOX) (2.3-fold) and mRNA(CYP4A2) (8-fold) and suppressed mRNA(FAS) and mRNA(S14) by greater than or equal to 80% in wild type mice, In PPAR alpha-deficient mice, PUFA did not induce mRNA(AOX) or mRNA(CYP4A2), indicating a requirement for PPAR alpha in the PUFA-mediated induction of these enzymes, However, PUFA still suppressed mRNA(FAS) and mRNA(S14) in the PPAR alpha-deficient mice, Studies in rats provided additional support for the differential regulation of lipogenic and peroxisomal enzymes by PUFA. These studies provide evidence for two distinct pathways for PUFA control of hepatic lipid metabolism. One requires PPAR alpha and is involved in regulating peroxisomal and microsomal enzymes, The other pathway does not require PPAR alpha and is involved in the PUFA mediated suppression of lipogenic gene expression.