Saturated non-esterified fatty acids stimulate de novo diacylglycerol synthesis and protein kinase c activity in cultured aortic smooth muscle cells

Diabetologia. 2001 May;44(5):614-20. doi: 10.1007/s001250051668.

Abstract

Aims/hypothesis: Insulin resistance is linked with a cluster of multiple risk factors and excessive acceleration of atherosclerosis. The underlying mechanism is not, however, fully understood.

Methods: To determine the link between insulin resistance and altered vascular function, we focused on the effect of various non-esterified fatty acids on diacylglycerol-protein kinase C pathway and mitogen-activated protein kinase activity in cultured aortic smooth muscle cells.

Results: Incubation of the cells with saturated non-esterified fatty acids (200 micromol/l) for 24 h, such as palmitate or stearate, induced a significant increase in diacylglycerol concentrations by about fivefold or eightfold, respectively, whereas oleate induced a slight increase in diacylglycerol concentrations by 1.8-fold and arachidonate induced none. In addition, the increased diacylglycerol concentrations induced by palmitate were completely restored to control concentrations by triacsin C, acyl-CoA synthetase inhibitor. These results suggest that saturated non-esterified fatty acids may increase diacylglycerol concentrations through de novo pathway by stepwise acylation. In parallel with the increased diacylglycerol, incubation of the cells with saturated non-esterified fatty acids significantly induced the activation of protein kinase C and mitogen-activated protein kinase. The palmitate-induced increase in mitogen-activated protein kinase activity was restored to control concentrations by GF109203X (5 x 10(-7) mol/l), a specific protein kinase C inhibitor, suggesting a protein kinase C-dependent activation of mitogen-activated protein kinase.

Conclusion/interpretation: Saturated non-esterified fatty acids induced an increase in de novo diacylglycerol synthesis and subsequent activation of protein kinase C and mitogen-activated protein kinase in cultured aortic smooth muscle cells. This could contribute to the altered vascular functions in the insulin resistant state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism*
  • Arachidonic Acid / pharmacology
  • Cattle
  • Cells, Cultured
  • Coenzyme A Ligases / antagonists & inhibitors
  • Diglycerides / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids, Nonesterified / pharmacology*
  • Indoles / pharmacology
  • Kinetics
  • Maleimides / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Oleic Acid / pharmacology
  • Palmitic Acid / pharmacology
  • Protein Kinase C / metabolism*
  • Stearic Acids / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Triazenes / pharmacology

Substances

  • Diglycerides
  • Enzyme Inhibitors
  • Fatty Acids, Nonesterified
  • Indoles
  • Maleimides
  • Stearic Acids
  • Triazenes
  • Arachidonic Acid
  • Oleic Acid
  • Palmitic Acid
  • stearic acid
  • triacsin C
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Coenzyme A Ligases
  • bisindolylmaleimide I
  • Tetradecanoylphorbol Acetate