Effects of fatty acids on hepatic gene expression.

Polyunsaturated fatty acids (PUFA) have dramatic effects on hepatic lipid metabolism by regulating the transcription of specific genes encoding enzymes involved in glycolysis and lipogenesis. The S14 gene, a putative lipogenic protein, has been used as a model to define the molecular basis of PUFA action on hepatic gene expression. We have shown that PUFA-regulated hepatic transcription factors target cis-regulatory elements located between -220 and -80 bp upstream from the 5' end of the S14 gene. Peroxisomal proliferators (PP) also have dramatic effects on hepatic lipid metabolism through effects on gene expression. The mechanism of PP action is mediated, at least in part, through nuclear receptors, i.e. PP activated receptor (PPAR). We found that the potent PP, i.e. WY14,643, suppressed mRNAS14 and the activity of an S14CAT fusion gene in cultured primary hepatocytes. Preliminary mapping studies showed that WY14,643 cis-regulatory elements were located either within the S14 proximal promoter (-290 and +19), the S14 TRE (-2900 to -2500) or both regions. Gel shift analysis showed that PPAR did not bind S14 promoter elements. These studies suggest that PUFA- and PP-regulated factors may share common cis-acting elements within the S14 promoter. However, if PUFA control of S14 gene transcription is mediated by PPAR, this mechanism does not involve direct interaction of PPAR with the S14 proximal promoter.