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Insulin Rapidly Induces Rat Liver S14 Gene Transcription

Cell and Molecular Biology Program, Physiology Department, Michigan State University East Lansing, Michigan 48824

Address requests for reprints to: Dr. Donald B. Jump, Cell and Molecular Biology Program, Physiology Department, Michigan State University, East Lansing, Michigan 48824.

Abstract

We evaluated the role insulin plays in the regulation of hepatic S14 gene transcription using the streptozotocin-induced diabetic rat model. Nuclear run-on activity and mRNA_S14 levels were reduced by more than 85% in diabetic rats compared to those in intact animals. After the administration of insulin, both S14 run-on activity and mRNA_S14 levels were rapidly induced. Within 1 h of insulin administration, S14 runon activity and mRNA_S14 were induced 5- and 8-fold, respectively. S14 gene expression was restored to intact levels within 4 h, with overall increases in runon activity and mRNA_S14 of 7- and 20-fold, respectively. The full induction of mRNA_S14 cannot be accounted for solely by activation of S14 gene transcription, implicating insulin effects at the posttranscriptional level. However, our results show that the principal target for insulin action on the S14 gene is transcriptional. Administration of dibutryl cAMP and theophylline fully blocked the insulin-mediated increase in S14 gene transcription, indicating that hepatic cAMP levels play a dominant negative role in regulating S14 gene transcription in vivo. Fructose administration to starved diabetic rats induced only a marginal 60% increase in mRNA_S14 and S14 runon activity within 4 h, while insulin plus fructose or insulin plus glucose fully restored S14 gene expression to intact levels within the same time period. Thus, dietary fructose or a metabolite generated from fructose alone cannot induce S14 gene transcription or mRNA_S14 to intact levels in the starved diabetic rat. Acute effects of dietary carbohydrate on hepatic S14 gene transcription are insulin dependent. In conclusion, our studies show that insulin plays a major positive role, while cAMP plays a dominant negative role in regulating hepatic S14 gene transcription in vivo.

FOOTNOTES

This work was supported by grants from the National Institute of General Medical Sciences (GM-36851) and the American Diabetes Association-Michigan Affiliate.

Received for publication July 2, 1990. Revision received August 13, 1990. Accepted for publication August 20, 1990.

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