POLYUNSATURATED FATTY-ACIDS REGULATE LIPOGENIC AND PEROXISOMAL GENE-EXPRESSION BY INDEPENDENT MECHANISMS

Polyunsaturated fatty acids of the (n-6) and (n-3) families uniquely c oordinate hepatic lipid synthesis and oxidation by suppressing the tra nscription 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 a ctivated nuclear transcription factors termed peroxisome proliferator activated receptors (PPARs) were cloned. The discovery of PPARs led us to hypothesize that polyunsaturated fatty acids coordinately modulate d the transcription of lipogenic and oxidative genes via a PPAR mediat ed process. Rats and mice were fed a potent PPAR activator, 5,8,11,14- eicosatetraynoic acid (ETYA), to ascertain if the expression of hepati c fatty acid synthase and peroxisomal acyl-CoA oxidase were coordinate ly suppressed and induced in response to PPAR activation. Expectedly, ETYA increased peroxisomal acyl-CoA oxidase mRNA abundance, but PPAR a ctivation neither suppressed fatty acid synthase transcription nor red uced the level of fatty acid synthase mRNA. In fact, ETYA prevented th e suppression of hepatic fatty acid synthase expression that character istically results from feeding corn oil. Fatty acid composition analys es 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 fo r the coordinate regulation of lipid synthesis and oxidation by polyun saturated fatty acids. In addition, our data indicate that the active polyenoic fatty acid responsible for the regulation of gene transcript ion must undergo delta-6 desaturation.