Gastric bypass surgery is protective from high‐fat diet‐induced non‐alcoholic fatty liver disease and hepatic endoplasmic reticulum stress

Abstract

Aim 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. Methods 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. Results 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). Conclusion 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.

Effect of Roux-en-Y gastric bypass on liver mitochondrial dynamics in a rat model of obesity

“…), we have previously reported reduced apoptosis in the liver of the same obese rats following RYGB surgery compared to Sham animals (Mosinski et al. ). These results suggest that BNIP3 may play a role in mitochondrial quality control independent of mitophagy, and future studies will be necessary to delineate whether alternative signaling pathways are involved.…”

“…Specifically, concomitant with a 20% decrease in body weight and a 57% improvement in insulin sensitivity (Mosinski et al. ), there was a significant increase in protein expression for Mfn1 ( P = 0.0005). Finally, reduced body weight was also associated with increased relative protein expression of BNIP3 (Fig.…”

“…; Mosinski et al. ). Briefly, sixteen 12‐week‐old SD rats (Charles River Laboratories, Wilmington, MA) were housed individually in a 12‐h light/dark cycle under constant ambient temperature (21–23°C) and humidity.…”

“…We have previously shown that bariatric surgery reduces insulin resistance and hepatic steatosis and inflammation from obese, non‐diabetic Sprague‐Dawley (SD) rats, and protects against endoplasmic reticulum (ER) stress and apoptosis (Mosinski et al. ). The specific cellular and molecular mechanisms by which re‐routing of the gut anatomy facilitates metabolic improvements in the liver is an area of active investigation.…”

Acta Physiologica Award: outperforming original articles from 2015 to 2017

“…To compensate for this obvious bias, the appearance date will be considered in the evaluation process. Our best performing articles in 2016 are currently . The latter two are from the same group!…”