Polyunsaturated fatty acids regulate lipogenic and peroxisomal gene expression by independent mechanisms

Polyunsaturated fatty acids of the (n-6) and (n-3) families uniquely coordinate hepatic lipid synthesis and oxidation by suppressing the transcription of hepatic genes encoding lipogenic and glycolytic enzymes while concomitantly inducing the activity of enzymes in mitochondrial and peroxisomal fatty acid oxidation. Recently a group of fatty acid activated nuclear transcription factors termed peroxisome proliferator activated receptors (PPARs) were cloned. The discovery of PPARs led us to hypothesize that polyunsaturated fatty acids coordinately modulated the transcription of lipogenic and oxidative genes via a PPAR mediated process. Rats and mice were fed a potent PPAR activator, 5,8,11,14-eicosatetraynoic acid (ETYA), to ascertain if the expression of hepatic fatty acid synthase and peroxisomal acyl-CoA oxidase were coordinately suppressed and induced in response to PPAR activation. Expectedly, ETYA increased peroxisomal acyl-CoA oxidase mRNA abundance, but PPAR activation neither suppressed fatty acid synthase transcription nor reduced the level of fatty acid synthase mRNA. In fact, ETYA prevented the suppression of hepatic fatty acid synthase expression that characteristically results from feeding corn oil. Fatty acid composition analyses indicated that ETYA interfered with 18:2 (n-6) conversion to 20:4 (n-6). Thus, it appears that PPAR is not the sole factor responsible for the coordinate regulation of lipid synthesis and oxidation by polyunsaturated fatty acids. In addition, our data indicate that the active polyenoic fatty acid responsible for the regulation of gene transcription must undergo delta-6 desaturation.