In vivo hormonal control of L-type pyruvate kinase gene expression. Effects of glucagon, cyclic AMP, insulin, cortisone, and thyroid hormones on the dietary induction of mRNAs in the liver.

A Munnich,J Marie,G Reach,S Vaulont,M P Simon,A Kahn

doi:10.1016/s0021-9258(18)90954-3

Abstract

Using a cDNA probe complementary to rat L-type pyruvate kinase mRNAs, we studied the respective roles of glucocorticoids, thyroid hormones, glucagon, and insulin in the induction of specific mRNAs in the liver of animals refed either a maltose-rich or a fructose-rich diet. Neither adrenalectomized nor thyroidectomized nor diabetic animals could express L-type pyruvate kinase mRNAs in their liver when refed the carbohydrate-rich diets. When the animals were given the missing hormone, the level of hybridizable mRNAs returned to normal values but administration of the hormone alone failed to induce mRNA synthesis in fasted animals. Both glucagon and cyclic AMP abolished the induction of L-type pyruvate kinase mRNAs in refed animals. Exogenous insulin, whatever the dose, could not reverse the inhibitory action of glucagon. Insulin has usually been regarded as the main regulator of L-type pyruvate kinase gene expression. It appears now that glucagon, beside regulating the enzyme activity by phosphorylation mechanisms, may also modulate L-type pyruvate kinase synthesis at a pre-translational level. Consequently, our results show that three conditions are required for the synthesis of liver L-type pyruvate kinase mRNAs: (i) the presence of dietary carbohydrates, (ii) the cessation of glucagon release, and (iii) the presence of permissive hormones, including insulin.

Highlights

From the Slnstitut National de la Sante et de la Recherche Medicale U.129, 24 rue du Fg St Jacques, 75674 Paris Cedex 14, France and the Unstitut National de la Santi et de la Recherche Medicab U.83, I O avenue de Verdun, 75010 Paris, France
Using a cDNA probe complementartoy rat L-type pyruvate kinasemRNAs [12], we quantitatedtheamount of cytoplasmic RNAs in the liver of normal, adrenalectomized, thyroidectomized, and diabetic animals refed the carbohydraterich diet
Cortisone, and thyroid hormonweesre found to exert a permissive effect ontheinduction of specific mRNAs but no induction occurred when normal fasted rats were given any of the hormones

Summary

DISCUSSION

Drates, (ii) the cessation of glucagon release, and (iii) Until recently, little was knownregarding the hormonal the presence of permissive hormones, including insu- control of liver L-type pyruvate kinase gene expression, eslin. Pyruvate kinase mRNAs in their liver, despite adequate food In conclusion, we show that beside its positive effect on the consumption.When refed animals were given the missing synthesis of a gluconeogenic enzyme,phosphoenolpyruvate hormones, thelevel of hybridizable material returned to nor- carboxykinase [34], glucagon and cyclic AMP negatively regmalvaluesbutnoinduction of specific mRNAs occurred ulate the gene expression of a glycolytic enzyme, L-type pyrwithout dietary carbohydrates. Three conditionsseem to be required ticoids, and thyroid hormones exert a “permissive effect” on for the full induction of liver L-type pyruvate kinasemRNAs: the induction of liver L-type pyruvate kinase mRNA synthe- (i) the presence of dietary carbohydrates as glycolytic subsis Both the hormones and thgelycolytic substrates (or their strates(ii)the cessation of glucagon release, and (iii) the metabolites)are requiredfor the full induction of specific presence of permissive hormones, including insulin. Acknowledgments-We thank Jean-Claude Dreyfus for his discussions, Claudine Brunner for typintghe manuscript, and AllanStrickland for his help in preparing it

Both rapid andlong acting glucagon were found to causea

Exogenous glucagon in high concentrationsis known to

Gene Expression