Chronic alcohol-induced hepatic insulin resistance and endoplasmic reticulum stress ameliorated by peroxisome-proliferator activated receptor-δ agonist treatment
Article first published online: 19 DEC 2012
© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Volume 28, Issue 1, pages 179–187, January 2013
How to Cite
Ramirez, T., Tong, M., Chen, W. C., Nguyen, Q.-G., Wands, J. R. and de la Monte, S. M. (2013), Chronic alcohol-induced hepatic insulin resistance and endoplasmic reticulum stress ameliorated by peroxisome-proliferator activated receptor-δ agonist treatment. Journal of Gastroenterology and Hepatology, 28: 179–187. doi: 10.1111/j.1440-1746.2012.07256.x
- Issue published online: 19 DEC 2012
- Article first published online: 19 DEC 2012
- Accepted manuscript online: 18 SEP 2012 07:56AM EST
- Manuscript Accepted: 10 AUG 2012
- alcoholic liver disease;
- endoplasmic reticulum stress;
- experimental model;
- insulin resistance;
- peroxisome-proliferator activated receptor agonists;
Background and Aim
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.
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.
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.
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.