EFFECTS OF FATTY-ACIDS ON HEPATIC GENE-EXPRESSION

Polyunsaturated fatty acids (PUFA) have dramatic effects on hepatic li pid metabolism by regulating the transcription of specific genes encod ing enzymes involved in glycolysis and lipogenesis. The S14 gene, a pu tative lipogenic protein, has been used as a model to define the molec ular basis of PUFA action on hepatic gene expression, We have shown th at PUFA-regulated hepatic transcription factors target cis-regulatory elements located between -220 and -80 bp upstream from the 5' end of t he S14 gene, Peroxisomal proliferators (PP) also have dramatic effects on hepatic lipid metabolism through effects on gene expression, The m echanism of PP action is mediated, at least in part, through nuclear r eceptors, i.e. PP activated receptor (PPAR). We found that the potent PP, i.e. WY14,643, suppressed mRNAs(S14) and the activity of an S14CAT fusion gene in cultured primary hepatocytes. Preliminary mapping stud ies showed that WY14,643 cis-regulatory elements were located either w ithin the S14 proximal promoter (-290 and +19), the S14 TRE (-2900 to -2500) or both regions, Gel shift analysis showed that PPAR did not bi nd S14 promoter elements, These studies suggest that PUFA- and PP-regu lated factors may share common cis-acting elements within the S14 prom oter, However, if PUFA control of S14 gene transcription is mediated b y PPAR, this mechanism does not involve direct interaction of PPAR wit h the S14 proximal promoter.