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Elevated glucose concentrations inhibit DNA synthesis and expression of c-myc in cultured hepatocytes

O F Dajani1, M Refsnes, T K Guren

  • 1Department of Pharmacology, Faculty of Medicine, University of Oslo, Blindern, Norway.

Biochemical and Biophysical Research Communications
|August 15, 1994
PubMed

Insights

High glucose levels inhibit rat hepatocyte DNA synthesis, specifically the D-form of glucose, by reducing c-myc gene expression. Cyclic AMP (cAMP) can counteract this glucose-induced inhibition.

Area of Science:

  • Hepatocyte biology
  • Molecular endocrinology
  • Cellular metabolism

Background:

  • Glucose is a primary energy source for cells.
  • Hepatocytes play a crucial role in glucose homeostasis.
  • Regulation of hepatocyte DNA synthesis is vital for liver function and regeneration.

Purpose of the Study:

  • To investigate the effect of elevated glucose concentrations on DNA synthesis in primary rat hepatocytes.
  • To explore the molecular mechanisms underlying glucose-mediated inhibition of hepatocyte proliferation.
  • To examine the role of specific signaling pathways, including cyclic AMP (cAMP), in modulating this response.

Main Methods:

  • Primary rat hepatocytes were cultured in media with varying glucose concentrations (5.6 mM to 30 mM).
  • DNA synthesis was measured using established assays.
  • Gene expression, specifically for the c-myc gene, was analyzed.
  • Hormonal responses (epidermal growth factor, insulin, vasopressin, glucagon) and the effect of 8-Br-cAMP were assessed.

Main Results:

  • Elevated glucose (10-30 mM) significantly inhibited hepatocyte DNA synthesis in a dose-dependent manner, with D-glucose being the active form.
  • Maximal inhibition of DNA synthesis occurred when glucose was present during the initial 24 hours of culture.
  • Reduced c-myc gene expression was observed under high glucose conditions.
  • Glucagon and 8-Br-cAMP counteracted the inhibitory effect of glucose on DNA synthesis.

Conclusions:

  • Increased glucose levels suppress hepatocyte DNA synthesis through a mechanism involving decreased c-myc gene expression.
  • The inhibitory effect of high glucose is specific to the D-isomer and requires initial exposure.
  • The cyclic AMP (cAMP) signaling pathway plays a critical role in reversing glucose-induced suppression of hepatocyte proliferation.

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