In euthyroid rats fed a high carbohydrate fat-free diet for 10 days, the mass of cellular malic enzyme mRNA in liver is increased 7- to 8-fold above the basal level. Malic enzyme activity is stimulated to the same extent. This effect does not result from an increase either in the transcriptional activity of the malic enzyme gene, as determined by nuclear run-off transcription assay, or in the content of intranuclear malic enzyme RNA sequences. Mathematical modeling shows that this increase in cytoplasmic mRNA is compatible with retarded degradation of cytoplasmic mRNA. Regulation of malic enzyme by carbohydrates is liver-specific, since no response is observed in the following nonhepatic tissues: brain, heart, spleen, kidney, testis, and lung. Furthermore, the amplitude of the response in liver depends on the thyroid state of the animals, being lower (by a factor of approximately 4) in hypothyroidism and higher (12- to 15-fold) when normal animals are injected simultaneously with a daily dose of 15 micrograms of triiodothyronine per 100 g of body weight for 10 days. Since thyroid hormones regulate liver malic enzyme synthesis predominantly at the nuclear level and carbohydrates at the cytoplasmic level, the additive effect of triiodothyronine and a high carbohydrate diet on the activity of malic enzyme is readily explicable.