POLYUNSATURATED FATTY-ACID INHIBITION OF FATTY-ACID SYNTHASE TRANSCRIPTION IS INDEPENDENT OF PPAR ACTIVATION

Polyunsaturated fatty acids (PUFA) of the (n-6) and (n-3) families inh ibit the rate of gene transcription for a number of hepatic lipogenic and glycolytic genes, e.g., fatty acid synthase (FAS). In contrast, sa turated and monounsaturated fatty acids have no inhibitory capability. The suppression of gene transcription resulting from the addition of PUFA to a high carbohydrate diet: occurs quickly ( < 3 h) after its ad dition to a high glucose diet; can be recreated with hepatocytes cultu red in a serum-free medium containing insulin and glucocorticoids; can be demonstrated in diabetic rats fed fructose; and is independent of glucagon. While the nature of the intracellular PUFA inhibitor is uncl ear, it appears that delta-6 desaturation is a required step in the pr ocess. Recently, the fatty acid activated nuclear factor, peroxisome-p roliferator activated receptor (PPAR) was suggested to be the PUFA-res ponse factor. However, the potent PPAR activators ETYA and Wy-14643 di d not suppress hepatic expression of FAS, but did induce the PPAR-resp onsive gene, acyl-CoA oxidase (AOX). Similarly, treating rat hepatocyt es with 20:4 (n-6) suppressed FAS expression but had no effect on AOX. Thus, it appears that the PUFA regulation of gene transcription invol ves a PUFA-response factor that is independent from PPAR.