Multiple mechanisms for polyunsaturated fatty acid regulation of hepatic gene transcription.

Dietary polyunsaturated fatty acids (PUFA) have profound effects on hepatic gene transcription leading to significant changes in lipid metabolism. Highly unsaturated n-3 PUFA suppress the transcription of genes encoding specific lipogenic enzymes and induce the expression of genes encoding specific enzymes involved in peroxisomal and microsomal fatty acid oxidation. Our studies have shown that fatty acid effects on hepatic gene expression may involve at least three distinct pathways. One pathway involves peroxisome proliferator-activated receptor (PPARalpha), a fatty acid activated nuclear receptor. PPARalpha is required for the PUFA induction of mRNAs encoding enzymes involved in fatty acid oxidation. However, PPARalpha is not required for PUFA suppression of mRNAs encoding proteins involved in lipogenesis. A second pathway involves prostanoids. In cultured 3T3-L1 adipocytes, cyclooxygenase derived 20:4 n-6 metabolites, like PGE2, suppress mRNAs encoding proteins involved in lipogenesis. However, in hepatic parenchymal cells, 20:4 n-6 suppression of lipogenic gene expression does not require a cyclooxygenase. Nevertheless, PGE2 and PGF2alpha suppress hepatic lipogenic gene expression. 20:4 n-6 cyclooxygenase products can arise from non-parenchymal cells and through a paracrine control process act on a G-protein linked receptor signaling cascade to suppress lipogenic gene expression. The fact that n-3 and n-6 PUFA suppression of lipogenic gene expression does not require PPARalpha or cyclooxygenase activity indicates the presence of a third pathway for the control of hepatic gene transcription. These studies indicate that the pleiotropic effects of PUFA on hepatic lipid metabolism cannot be attributed to a single regulatory mechanism.