title: Chronic alcohol-induced hepatic insulin resistance and endoplasmic reticulum stress ameliorated by peroxisome-proliferator activated receptor-δ agonist treatment.
abstract: OBJECTIVE
  Chronic alcoholic liver disease is associated with hepatic insulin resistance, dysregulated lipid metabolism with increased toxic lipid (ceramide) accumulation, lipid peroxidation, and oxidative and endoplasmic reticulum (ER) stress. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that can restore hepatic insulin responsiveness in both alcohol and non-alcohol-related steatohepatitis. Herein, we demonstrate that treatment with a PPAR-δ agonist enhances insulin signaling and reduces the severities of ER stress and ceramide accumulation in an experimental model of ethanol-induced steatohepatitis.
  
  
  METHODS
  Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle or PPAR-δ agonist twice weekly by i.p. injection.
  
  
  RESULTS
  Ethanol-fed rats developed steatohepatitis with inhibition of signaling through the insulin and insulin-like growth factor-1 receptors, and Akt activated pathways. Despite continued ethanol exposure, PPAR-δ agonist co-treatments increased Akt activation, reduced multiple molecular indices of ER stress and steatohepatitis.
  
  
  CONCLUSIONS
  These results suggest that PPAR-δ agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt/metabolic pathways that reduce lipotoxicity and ER stress.
authors.affiliation: Liver Research Center and Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramirez
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.forename: William Cy
authors.initials: WC
authors.lastname: Chen
authors.forename: Quynh-Giao
authors.initials: QG
authors.lastname: Nguyen
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002518:Ceramides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure*; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D047494:PPAR delta / Q000819:agonists*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D002518:Ceramides; D055504:Insulin Receptor Substrate Proteins; D047494:PPAR delta; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt