Polyunsaturated fatty acids inhibit the expression of the glucose-6-phosphate dehydrogenase gene in primary rat hepatocytes by a nuclear posttranscriptional mechanism

Expression of the glucose-6-phosphate dehydro- genase (G6PD) gene is inhibited by the addition of polyun- saturated fatty acids to the medium of primary hepatocytes in culture. To define the regulated step, we measured the abundance of G6PD mRNA both in the nucleus and in total RNA and measured the transcriptional activity of the G6PD gene. Insulin and glucose stimulated a 5- to 7-fold increase in G6PD mRNA in rat hepatocytes. This increase was atten- uated by 60% due to the addition of arachidonic acid. These changes in mRNA accumulation occurred in the ab- sence of changes in the rate of transcription. Amounts of precursor mRNA (pre-mRNA) for G6PD in the nucleus changed in parallel with the amount of mature mRNA. The decrease in G6PD pre-mRNA accumulation caused by arachidonic acid was also observed with other long chain polyunsaturated fatty acids but not with monounsaturated fatty acids. In addition, this decrease was not due to a gen- eralized toxicity of the cells due to fatty acid oxidation. These changes in G6PD expression in the primary hepato- cytes are qualitatively and quantitatively similar to the changes observed in the intact animal due to dietary carbo- hydrate and polyunsaturated fat. Regulation of G6PD ex- pression by a nuclear posttranscriptional mechanism repre- sents a novel form of regulation by fatty acids.— Stabile, L. P., S. A. Klautky, S. M. Minor, and L. M. Salati. Polyunsat- urated fatty acids inhibit the expression of the glucose-6- phosphate dehydrogenase gene in primary rat hepatocytes by a nuclear posttranscriptional mechanism. J. Lipid Res. 1998. 39: 1951-1963.