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Area of Science:

  • Metabolic disease
  • Hepatology
  • Molecular biology

Background:

  • Long-term nutritional excess causes hepatic steatosis, endoplasmic reticulum (ER) stress, hyperglycemia, and hyperlipidemia.
  • Mitogen-activated protein kinase phosphatase-3 (MKP-3) regulates gluconeogenesis and is stress-responsive.
  • The role of MKP-3 in chronic ER stress and its regulatory mechanisms remain unclear.

Purpose of the Study:

  • Investigate the effects of chronic ER stress on hepatic MKP-3 expression.
  • Determine the role of MKP-3 in regulating gluconeogenesis under chronic ER stress.
  • Elucidate the molecular pathway linking chronic ER stress, MKP-3, and hepatic gluconeogenesis.

Main Methods:

  • Primary mouse hepatocytes treated with thapsigargin (Tg) or palmitic acid.
  • Mice subjected to long-term high-fat diet (HFD) or Tg administration.
  • Liver-specific MKP-3 knockout (LKO) mouse model.
  • PERK pathway activation and inhibition studies.

Main Results:

  • Long-term Tg or palmitic acid promoted hepatic Mkp-3 and gluconeogenic gene expression (Pepck, G6pc, Pgc1α).
  • HFD or Tg increased hepatic ER stress, blood glucose, Mkp-3, and gluconeogenic gene expression in mice.
  • Liver-specific Mkp-3 knockout reversed HFD-induced hyperglycemia and gluconeogenic gene expression.
  • PERK activation increased hepatic Mkp-3 expression; PERK inhibition suppressed Mkp-3 under Tg treatment.

Conclusions:

  • Chronic ER stress, induced by HFD, promotes hepatic gluconeogenesis via the PERK/MKP-3 pathway.
  • MKP-3 plays a critical role in HFD-induced hyperglycemia.
  • The PERK/MKP-3 pathway represents a potential therapeutic target for obesity-related hyperglycemia.