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Homocysteine activates cAMP-response element binding protein in HepG2 through cAMP/PKA signaling pathway

Connie W H Woo1, Yaw L Siow, Karmin O

  • 1Department of Animal Science, University of Manitoba, Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada.

Arteriosclerosis, Thrombosis, and Vascular Biology
|February 25, 2006
PubMed

Insights

High homocysteine levels activate the cAMP/PKA pathway, leading to CREB activation in liver cells. This molecular mechanism contributes to cardiovascular risks associated with hyperhomocysteinemia.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Hyperhomocysteinemia is a known risk factor for cardiovascular diseases.
  • Previous research linked hyperhomocysteinemia to vascular inflammation, fatty liver, and hypercholesterolemia through transcriptional regulation.
  • cAMP-response element binding protein (CREB) is a transcription factor activated during hyperhomocysteinemia, influencing lipid and glucose metabolism.

Purpose of the Study:

  • To investigate the molecular mechanism by which homocysteine (Hcy) activates CREB in rat liver and HepG2 hepatocytes.
  • To elucidate the role of the cAMP/PKA signaling pathway in Hcy-induced CREB activation.

Main Methods:

  • Hyperhomocysteinemia was induced in rats using a high-methionine diet.
  • HepG2 cells were incubated with varying concentrations of Hcy.
  • Measurements included hepatic cAMP levels, protein kinase A (PKA) activity, CREB phosphorylation, and CREB/DNA binding activity.
  • Adenylyl cyclase inhibition was used to assess pathway involvement.

Main Results:

  • Hyperhomocysteinemia in rats led to increased hepatic cAMP, PKA activity, and CREB activation.
  • Hcy treatment in HepG2 cells significantly enhanced CREB phosphorylation and DNA binding activity.
  • Hcy elevated intracellular cAMP levels, activating PKA in hepatocytes.
  • Inhibiting adenylyl cyclase blocked Hcy-induced PKA activation and CREB phosphorylation.

Conclusions:

  • The cAMP/PKA signaling pathway is crucial for mediating homocysteine-induced CREB activation in hepatocytes.
  • Understanding this mechanism provides insight into the molecular basis of cardiovascular risks associated with hyperhomocysteinemia.
Abstract

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