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

Polyunsaturated fatty acids (PUFAs) have been shown to have significan t effects on hepatic lipogenic gene expression. The S14 gene has been used as a model to examine the effects of PUFAs on hepatic lipogenic g ene expression. In vivo studies showed that feeding rats a high carboh ydrate diet containing menhaden oil rapidly (within hours) and signifi cantly (greater-than-or-equal-to 50%) attenuates hepatic S14 gene tran scription and S14 mRNA abundance. The suppressive effect of menhaden o il was both gene and tissue specific. The effect of PUFAs on expressio n of the S14 mRNA and a transfected S14 fusion gene (i.e., S14CAT4.3) was examined in cultured hepatocytes in the presence of triiodothyroni ne (T3), insulin, dexamethasone, and albumin under serum-free conditio ns. 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 d ose-dependent fashion. The effects of C20:5 on hepatocyte gene express ion were both gene and fatty acid specific. Deletion analysis of trans fected S14CAT fusion genes indicated that the S14 thyroid hormone resp onse 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 withi n the S14 proximal promoter (at -80 to -220 bp). This region also cont ains cis-acting elements that potentiate T3 activation of S14 gene tra nscription. These studies suggest that C20:5 (or its metabolites) regu lates factors within the S14 proximal promoter region that are importa nt for T3 activation of S14 gene transcription.