title: Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway.
abstract: OBJECTIVE
  Glucagon-like peptide-1 (GLP-1) has been increasingly recognized for treating diabetes mellitus, and for its potential to effectively treat non-alcoholic fatty liver disease (NAFLD). However, the mechanisms of GLP-1 induction in NAFLD are not completely known. We investigated whether GLP-1 can protect against NAFLD by alleviating endoplasmic reticulum (ER) stress.
  
  
  METHODS
  Male Sprague-Dawley rats were fed a high-fat diet and treated with a long-acting GLP-1 receptor agonist, liraglutide. Biochemical, morphological, genetic and protein expression of ER stress were investigated. In vitro, HepG2 cells were exposed to 0.4 mM palmitate fatty acid and treated with different concentrations of GLP-1, and ER protein 46 (ERp46) and ER stress pathways were analyzed. Cellular response to ER stress and apoptosis were determined upon transfection with either ERp46 siRNA or a negative control siRNA.
  
  
  RESULTS
  In vivo, the treatment of GLP-1 attenuated the hepatic accumulation of lipids, reduced inflammation and improved metabolic parameters. GLP-1 treatment significantly upregulated the expression of ERp46 and downregulated the ER stress marker. Activation of ER pathways was restrained by GLP-1. Similar observations were made in vitro. Furthermore, inhibition of ERp46 expression by siRNA-mediated silencing increased the ER stress response and enhanced cell apoptosis rates. In addition, GLP-1 could not reduce the levels of ER stress and apoptosis in cells transfected with ERp46 siRNA compared with in negative control transfected cells after palmitate treatment.
  
  
  CONCLUSIONS
  GLP-1 protected against NAFLD by inactivating the ER stress-associated apoptosis pathway. In addition, the effect was possibly related to the signaling pathway of ERp46.
authors.affiliation: Department of Endocrinology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Na
authors.initials: N
authors.lastname: Ao
authors.affiliation: Department of Endocrinology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Du
keywords: apoptosis; endoplasmic reticulum protein 46; endoplasmic reticulum stress; glucagon-like peptide-1; non-alcoholic fatty liver disease