POLYUNSATURATED FATTY-ACIDS INHIBIT S14 GENE-TRANSCRIPTION IN RAT-LIVER AND CULTURED-HEPATOCYTES

Polyunsaturated fatty acids (PUFAs) have been shown to have significant effects on hepatic lipogenic gene expression. The S14 gene has been used as a model to examine the effects of PUFAs on hepatic lipogenic gene expression. In vivo studies showed that feeding rats a high carbohydrate diet containing menhaden oil rapidly (within hours) and significantly (greater-than-or-equal-to 50%) attenuates hepatic S14 gene transcription and S14 mRNA abundance. The suppressive effect of menhaden oil was both gene and tissue specific. The effect of PUFAs on expression of the S14 mRNA and a transfected S14 fusion gene (i.e., S14CAT4.3) was examined in cultured hepatocytes in the presence of triiodothyronine (T3), insulin, dexamethasone, and albumin under serum-free conditions. Whereas T3 Stimulated both S14 mRNA (>40-fold) and S14CAT4.3 (>100-fold), eicosapentaenoic acid (C20:5omega3) significantly attenuated (greater-than-or-equal-to 80%) both S14 mRNA and S14CAT activity in a dose-dependent fashion. The effects of C20:5 on hepatocyte gene expression were both gene and fatty acid specific. Deletion analysis of transfected S14CAT fusion genes indicated that the S14 thyroid hormone response element (at -2.5 to -2.9 kb) was not sensitive to C20:5 control. The cis-linked PUFA response elements were localized to a region within the S14 proximal promoter (at -80 to -220 bp). This region also contains cis-acting elements that potentiate T3 activation of S14 gene transcription. These studies suggest that C20:5 (or its metabolites) regulates factors within the S14 proximal promoter region that are important for T3 activation of S14 gene transcription.