Cell Stress and Chaperones

, Volume 19, Issue 5, pp 649–656

Exendin-4 attenuates endoplasmic reticulum stress through a SIRT1-dependent mechanism

  • Jinmi Lee
  • Seok-Woo Hong
  • Se Eun Park
  • Eun-Jung Rhee
  • Cheol-Young Park
  • Ki-Won Oh
  • Sung-Woo Park
  • Won-Young Lee
Original Paper

DOI: 10.1007/s12192-013-0490-3

Cite this article as:
Lee, J., Hong, SW., Park, S.E. et al. Cell Stress and Chaperones (2014) 19: 649. doi:10.1007/s12192-013-0490-3

Abstract

Accumulation of excess hepatic lipids contributes to insulin resistance and liver disease associated with endoplasmic reticulum (ER) stress. Exendin-4 is an agonist of the glucagon-like peptide 1 receptor and plays a role in improving insulin resistance and liver disease by increasing silent mating type information regulation 2 homolog (SIRT) 1. However, the effects and mechanism of action of exendin-4 on responses to palmitic acid (PA)-induced ER stress in hepatocytes have not been clearly defined. We investigated whether exendin-4 attenuates PA-induced ER stress via SIRT1 in HepG2 cells. PA treatment induced increased expression of PRKR-like endoplasmic reticulum kinase, inositol-requiring kinase 1α (IRE1α), activating transcription factor 6 (ATF6), and C/EBP homologous protein (CHOP) mRNA. Exendin-4 decreased the expression of P-IRE1α, ATF6, X-box binding protein-1 and CHOP, and increased the expression of SERCA2b. A significant decrease in the hepatic expression of PUMA, BAX, cytochrome c, and cleaved caspase-3 were observed in hepatocytes treated with exendin-4. The TUNEL assay consistently showed that exendin-4 reversed hepatocyte apoptosis induced by treatment with PA. Inhibition of SIRT1 by nicotinamide and siRNA significantly increased the expression of ER stress marker genes in cells treated with both PA and exendin-4. In conclusion, increased SIRT1 by exendin-4 attenuates PA-induced ER stress and mitochondrial dysfunction in hepatocytes.

Keywords

Exendin-4SIRT1ER stressMitochondrial dysfunctionApoptosisHepatocyte

Copyright information

© Cell Stress Society International 2014

Authors and Affiliations

  • Jinmi Lee
    • 1
  • Seok-Woo Hong
    • 1
  • Se Eun Park
    • 2
  • Eun-Jung Rhee
    • 2
  • Cheol-Young Park
    • 2
  • Ki-Won Oh
    • 2
  • Sung-Woo Park
    • 2
  • Won-Young Lee
    • 2
    • 3
  1. 1.Institute of Medical Research, Kangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Division of Endocrinology and Metabolism, Kangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulSouth Korea
  3. 3.Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulSouth Korea