title: Exendin-4 Inhibits the Expression of SEPP1 and Fetuin-A via Improvement of Palmitic Acid-Induced Endoplasmic Reticulum Stress by AMPK.
abstract: BACKGROUND
  Selenoprotein P (SEPP1) and fetuin-A, both circulating liver-derived glycoproteins, are novel biomarkers for insulin resistance and nonalcoholic fatty liver disease. However, the effect of exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, on the expression of hepatokines, SEPP1, and fetuin-A, is unknown.
  
  
  METHODS
  The human hepatoma cell line HepG2 was treated with palmitic acid (PA; 0.4 mM) and tunicamycin (tuni; 2ug/ml) with or without exendin-4 (100 nM) for 24 hours. The change in expression of PA-induced SEPP1, fetuin-A, and endoplasmic reticulum (ER) stress markers by exendin-4 treatment were evaluated using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. Transfection of cells with AMP-activated protein kinase (AMPK) small interfering RNA (siRNA) was performed to establish the effect of exendin-4-mediated AMPK in the regulation of SEPP1 and fetuin-A expression.
  
  
  RESULTS
  Exendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositol-requiring kinase 1α, activating transcription factor 6, and C/EBP homologous protein in HepG2 cells. Exendin-4 also reduced the expression of SEPP1 and fetuin-A in cells treated with tunicamycin, an ER stress inducer. In cells treated with the AMPK activator 5-aminoidazole-4-carboxamide ribonucleotide (AICAR), the expression of hepatic SEPP1 and fetuin-A were negatively related by AMPK, which is the target of exendin-4. In addition, exendin-4 treatment did not decrease SEPP1 and fetuin-A expression in cells transfected with AMPK siRNA.
  
  
  CONCLUSIONS
  These data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jinmi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Seok Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Rhee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Cheol Young
authors.initials: CY
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. drlwy@hanmail.net.
authors.forename: Won Young
authors.initials: WY
authors.lastname: Lee
keywords: AMP-activated protein kinases; Endoplasmic reticulum stress; Exendin-4; Fetuin-A; Hepatokine; Palmitic acid; Selenoprotein P