Azoramide ameliorates fructose-induced nonalcoholic fatty liver disease in mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a frequent health problem. The insulin resistance and endoplasmic reticulum (ER) stress have been suggested to play important roles in the development and progression of NAFLD. However these processes and correlations have not fully been understood yet. Azoramide, an antidiabetic drug, has the potential for reducing insulin resistance and ER stress in obese mice. To date, there is no study on the effects of azoramide in NAFLD. The aim of this study was to investigate the potential role of azoramide on insulin resistance and ER stress in NAFLD induced mice. Forty Swiss Albino mice were assigned into control, azoramide, fructose and fructose + azoramide groups. Azoramide group received a single dose of azoramide at 150 mg/kg/day by gavage between 71-77th days. Fructose group was treated with 30% fructose solution for 70 days to generate NAFLD. Fructose + azoramide group was treated with 30% fructose for 70 days and then with a single dose of 150 mg/kg/day azoramide for 7 days. At the end of experiment, blood of mice was taken via cardiac puncture, and the livers were excised and weighted. GRP78 and XBP-1 levels were examined with immunohistochemistry in liver tissues. Liver steatosis was evaluated with H&E, Oil-Red O and Sudan-Black staining. ALT, AST, triglyceride, total cholesterol, VLDL, LDL, HDL, fasting glucose and insulin levels were measured in serum. The body and liver weights, insulin resistance, ER-stress markers, lipid profile, AST, ALT and histopathological changes increased by fructose treatment. Azoramide treatment was generally reversed all these changes. These data offer the first evidence to show that azoramide may serve as a potential treatment agent in NAFLD through decreasing the ER-stress and insulin resistance.

Keywords: Azoramide; Endoplasmic reticulum stress; GRP78; Insulin resistance; Nonalcoholic fatty liver disease; Steatosis.