Chronic alcohol-induced hepatic insulin resistance and endoplasmic reticulum stress ameliorated by peroxisome-proliferator activated receptor-δ agonist treatment.

Abstract:

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. 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

Ramirez T,Tong M,Chen WC,Nguyen QG,Wands JR,de la Monte SM

doi

10.1111/j.1440-1746.2012.07256.x

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

179-87

issue

1

eissn

0815-9319

issn

1440-1746

journal_volume

28

pub_type

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