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 dehydrogenase (G6PD) gene is inhibited by the addition of polyunsaturated 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 attenuated by 60% due to the addition of arachidonic acid. These changes in mRNA accumulation occurred in the absence 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 generalized toxicity of the cells due to fatty acid oxidation. These changes in G6PD expression in the primary hepatocytes are qualitatively and quantitatively similar to the changes observed in the intact animal due to dietary carbohydrate and polyunsaturated fat. Regulation of G6PD expression by a nuclear posttranscriptional mechanism represents a novel form of regulation by fatty acids.