Nutritional Regulation of the Glucose-6-Phosphate Dehydrogenase Gene Is Mediated by a Nuclear Posttranscriptional Mechanism

Expression of the glucose-6-phosphate dehydrogenase (G6PD) gene is inhibited by addition of polyunsaturated fat to a high-carbohydrate diet and stimulated by feeding a high-carbohydrate diet to starved mice. The mechanism of this regulation is posttranscriptional. To define the regulated step, we measured the abundance of G6PD mRNA both in the nucleus and in total RNA. Feeding mice a high-fat diet results in a 70% or greater inhibition of nuclear precursor mRNA (pre-mRNA) and mature mRNA abundance. Amounts of both pre-mRNA and mature mRNA for G6PD are stimulated 13-fold or more by refeeding starved mice. Changes in amount of pre-mRNA for G6PD are of a similar magnitude and precede the changes in amount of mature mRNA for G6PD in total RNA. These changes in pre-mRNA abundance occur in the absence of observable changes in the rate of transport of mRNA from the nucleus to the cytoplasm, splicing of the pre-mRNA, or degradation at the 3′-end of the transcript. Despite large changes in pre-mRNA amount in mice fed a low-fat diet relative to mice fed a high-fat diet, the rate of change in the amount of pre-mRNA during the diurnal feeding cycle is not altered. Thus, expression of G6PD is regulated at an early step after transcription of the pre-mRNA. We suggest that pre-mRNA which enters the processing pathway is stable and can be processed and transported to the cytoplasm where it is translated.