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Poly(ADP-ribose) polymerase 1 is involved in glucose toxicity through SIRT1 modulation in HepG2 hepatocytes

Jing Pang1, Huan Gong, Chao Xi

  • 1Chinese Academy of Medical Sciences, China.

Journal of Cellular Biochemistry
|October 30, 2010
PubMed

Insights

High glucose levels trigger oxidative stress and DNA damage, contributing to glucose toxicity. This study reveals that poly(ADP-ribose) polymerase 1 (PARP1) activation exacerbates glucose toxicity by impairing SIRT1, AMPK, and insulin signaling.

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Metabolism

Background:

  • Accelerated glucose metabolism causes oxidative stress and DNA damage, contributing to cellular glucose toxicity.
  • The exact mechanisms underlying glucose toxicity remain incompletely understood.
  • Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA repair enzyme activated by oxidative stress.

Purpose of the Study:

  • To investigate the role of PARP1 activation in high-glucose-induced toxicity in HepG2 hepatocytes.
  • To elucidate the downstream effects of PARP1 activation on cellular signaling pathways and insulin sensitivity.

Main Methods:

  • HepG2 cells were cultured under normal (5.5 mM) and high (30 mM) glucose conditions.
  • PARP1 activity was assessed, along with reactive oxygen species (ROS) generation and DNA damage.
  • The effects of a PARP1 inhibitor (PJ34) and small interfering RNA (siRNA) targeting PARP1 were evaluated.
  • SIRT1, AMP-activated protein kinase (AMPK) activity, nicotinamide adenine dinucleotide (NAD) content, and insulin receptor phosphorylation were measured.

Main Results:

  • High glucose significantly increased PARP1 activity, ROS generation, and DNA damage in HepG2 cells.
  • PARP1 inhibition or knockdown prevented the suppression of SIRT1 and AMPK activity and restored NAD+ levels.
  • PARP1 inhibition reversed the impaired insulin receptor phosphorylation observed under high glucose conditions.

Conclusions:

  • High-glucose-induced PARP1 activation contributes to glucose toxicity.
  • PARP1 activation down-regulates SIRT1 and AMPK activity via NAD+ depletion, leading to insulin insensitivity.

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