title: Gastric bypass surgery is protective from high-fat diet-induced non-alcoholic fatty liver disease and hepatic endoplasmic reticulum stress.
abstract: High-fat diets are known to contribute to the development of obesity and related co-morbidities including non-alcoholic fatty liver disease (NAFLD). The accumulation of hepatic lipid may increase endoplasmic reticulum (ER) stress and contribute to non-alcoholic steatohepatitis and metabolic disease. We hypothesized that bariatric surgery would counter the effects of a high-fat diet (HFD) on obesity-associated NAFLD.
  
  
  
  Sixteen of 24 male Sprague Dawley rats were randomized to Sham (N = 8) or Roux-en-Y gastric bypass (RYGB) surgery (N = 8) and compared to Lean controls (N = 8). Obese rats were maintained on a HFD throughout the study. Insulin resistance (HOMA-IR), and hepatic steatosis, triglyceride accumulation, ER stress and apoptosis were assessed at 90 days post-surgery.
  
  
  
  Despite eating a HFD for 90 days post-surgery, the RYGB group lost weight (-20.7 ± 6%, P < 0.01) and improved insulin sensitivity (P < 0.05) compared to Sham. These results occurred with no change in food intake between groups. Hepatic steatosis and ER stress, specifically glucose-regulated protein-78 (Grp78, P < 0.001), X-box binding protein-1 (XBP-1) and spliced XBP-1 (P < 0.01), and fibroblast growth factor 21 (FGF21) gene expression, were normalized in the RYGB group compared to both Sham and Lean controls. Significant TUNEL staining in liver sections from the Obese Sham group, indicative of accelerated cell death, was absent in the RYGB and Lean control groups. Additionally, fasting plasma glucagon like peptide-1 was increased in RYGB compared to Sham (P < 0.02).
  
  
  
  These data suggest that in obese rats, RYGB surgery protects the liver against HFD-induced fatty liver disease by attenuating ER stress and excess apoptosis.
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Mosinski
authors.affiliation: Department of Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Pagadala
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mulya
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Bariatric Metabolic Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: O
authors.initials: O
authors.lastname: Dan
authors.affiliation: Department of Bariatric Metabolic Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Bariatric Metabolic Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Batayyah
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Pai
authors.affiliation: Department of Bariatric Metabolic Institute, Cleveland Clinic, Cleveland, OH, USA.|Metabolic Translational Research Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Schauer
authors.affiliation: Department of Bariatric Metabolic Institute, Cleveland Clinic, Cleveland, OH, USA.|Metabolic Translational Research Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Brethauer
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA.|Department of Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, OH, USA.|Metabolic Translational Research Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Kirwan
mesh_terms: D000818:Animals; D017209:Apoptosis; D059305:Diet, High-Fat / Q000009:adverse effects*; D059865:Endoplasmic Reticulum Stress; D015390:Gastric Bypass; D050356:Lipid Metabolism; D008099:Liver / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
keywords: NAFLD; RYGB; apoptosis; obesity; rats