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Cell Stress and Chaperones

, Volume 23, Issue 4, pp 629–638 | Cite as

Exendin-4 improves ER stress-induced lipid accumulation and regulates lipin-1 signaling in HepG2 cells

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

Abstract

Lipin-1 performs dual function during lipid metabolism, i.e., it functions as a transcriptional coactivator and as a phosphatidate phosphatase during triglyceride biosynthesis. We investigated whether exendin-4 prevented endoplasmic reticulum (ER) stress-induced hepatic steatosis and whether the protective effects of exendin-4 were associated with lipin-1 signaling. Tunicamycin and thapsigargin, ER stress inducers, increased triglycerides (TG) content and expression of genes encoding lipid droplet surface proteins. Exendin-4 decreased the expression of ER stress markers phosphorylated PKR like ER kinase (PERK), phosphorylated inositol-requiring enzyme 1 alpha (IRE1α), and glucose-regulated protein 78 kDa (GRP78) proteins and spliced X-box binding protein 1 (XBP-1s) mRNA and increased the expression of genes encoding lipolytic enzymes hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL) and VLDL assembly-associated proteins microsomal triglyceride transfer protein (MTP) and apolipoprotein B (APOB) in tunicamycin-pretreated cells. Moreover, exendin-4 significantly decreased lipin-1β/α ratio by increasing SFRP10 and increased lipin-1 nuclear localization. The decrease in lipin-1β/α ratio was also observed in SIRT1 and AMPK agonist-treated cells. These data suggest that exendin-4 improves ER stress-induced hepatic lipid accumulation by increasing lipolysis and VLDL assembly, which is partially mediated by the regulation of lipin-1 signaling.

Keywords

Exendin-4 ER stress Lipid accumulation Lipolysis VLDL assembly Lipin-1 

Abbreviations

AMPK

AMP-activated protein kinase

APOB

Apolipoprotein B

ATGL

Adipose tissue triglyceride lipase

CIDEC

Cell death-inducing DFFA-like effector c

ER

Endoplasmic reticulum

GLP-1

Glucagon-like protein-1

GRP78

Glucose-regulated protein 78 kDa

HSL

Hormone-sensitive lipase

IRE1α

Inositol-requiring enzyme 1 alpha

MGL

Monoacylglycerol lipase

MTP

Microsomal triglyceride transfer protein

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

PA

Palmitic acid

PERK

PKR like ER kinase

PKA

Protein kinase A

PLIN

Perilipin

SFRS10

Serine-arginine-rich splicing factor 10

SIRT1

Silent mating-type information regulation 2 homolog 1

SREBP-1

Sterol regulatory element-binding protein 1

TG

Triglycerides

VLDL

Very-low-density lipoprotein

XBP-1

X-box binding protein 1

Notes

Acknowledgments

This study was supported by Samsung Biomedical Research Institute (SBRI) (http://www.sbri.or.kr), the Medical Research Funds from Kangbuk Samsung Hospital, and the National Research Foundation (NRF), which is funded by the Korean government (NRF-2016R1A6A3A11930792) (http://www.nrf.re.kr). The funders had no role in the study design, data collection, and analysis, the decision to publish, or preparation of the manuscript.

Supplementary material

12192_2017_872_MOESM1_ESM.pdf (200 kb)
ESM 1 (PDF 199 kb)

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Copyright information

© Cell Stress Society International 2018

Authors and Affiliations

  • Jinmi Lee
    • 1
  • Seok-Woo Hong
    • 1
  • Hyemi Kwon
    • 2
  • 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 MedicineSeoulRepublic of Korea
  2. 2.Department of Endocrinology and Metabolism, Kangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulRepublic of Korea
  3. 3.Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulRepublic of Korea

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