Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2016; 22(10): 2931-2948
Published online Mar 14, 2016. doi: 10.3748/wjg.v22.i10.2931
Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression
Enas A Abd El-Haleim, Ashraf K Bahgat, Samira Saleh
Enas A Abd El-Haleim, Ashraf K Bahgat, Samira Saleh, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
Samira Saleh, Currently Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 11835, Egypt
Author contributions: Abd El-Haleim EA performed the literature search, practical work and writing the manuscript; Bahgat AK and Saleh S were responsible for conception and design of study, analysis and interpretation of data, contributed in writing the manuscript and critical revision for important intellectual content, and final approval of the article.
Institutional review board statement: The research ethics committee for experimental and clinical studies at Faculty of Pharmacy, Cairo University, Cairo, Egypt has approved the research protocol. In the faculty of Pharmacy, Cairo University, The institutional review board (IRB) is called the Ethics committee (EC). It reviews all the aspects of basic research including animal care, or clinical trials approving their startup.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Faculty of Pharmacy, Cairo University (IACUC protocol number: 660).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest to disclose.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at [enaselshemy@hotmail.com]. Participants gave informed consent for data sharing. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Enas A Abd El-Haleim, MSc, Assistant Lecturer of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo University Rd, Cairo 11562, Egypt. enaselshemy@hotmail.com
Telephone: +20-2-23639307 Fax: +20-2-23628426
Received: June 10, 2015
Peer-review started: June 12, 2015
First decision: November 5, 2015
Revised: December 4, 2015
Accepted: January 9, 2016
Article in press: January 11, 2016
Published online: March 14, 2016
Abstract

AIM: To evaluate the effect of resveratrol, alone and in combination with fenofibrate, on fructose-induced metabolic genes abnormalities in rats.

METHODS: Giving a fructose-enriched diet (FED) to rats for 12 wk was used as a model for inducing hepatic dyslipidemia and insulin resistance. Adult male albino rats (150-200 g) were divided into a control group and a FED group which was subdivided into 4 groups, a control FED, fenofibrate (FENO) (100 mg/kg), resveratrol (RES) (70 mg/kg) and combined treatment (FENO + RES) (half the doses). All treatments were given orally from the 9th week till the end of experimental period. Body weight, oral glucose tolerance test (OGTT), liver index, glucose, insulin, insulin resistance (HOMA), serum and liver triglycerides (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST, ALT, AST/ALT ratio and tumor necrosis factor-α (TNF-α) were measured. Additionally, hepatic gene expression of suppressor of cytokine signaling-3 (SOCS-3), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), malonyl CoA decarboxylase (MCD), transforming growth factor-β1 (TGF-β1) and adipose tissue genes expression of leptin and adiponectin were investigated. Liver sections were taken for histopathological examination and steatosis area were determined.

RESULTS: Rats fed FED showed damaged liver, impairment of glucose tolerance, insulin resistance, oxidative stress and dyslipidemia. As for gene expression, there was a change in favor of dyslipidemia and nonalcoholic steatohepatitis (NASH) development. All treatment regimens showed some benefit in reversing the described deviations. Fructose caused deterioration in hepatic gene expression of SOCS-3, SREBP-1c, FAS, MDA and TGF-β1 and in adipose tissue gene expression of leptin and adiponectin. Fructose showed also an increase in body weight, insulin resistance (OGTT, HOMA), serum and liver TGs, hepatic MDA, serum AST, AST/ALT ratio and TNF-α compared to control. All treatments improved SOCS-3, FAS, MCD, TGF-β1 and leptin genes expression while only RES and FENO + RES groups showed an improvement in SREBP-1c expression. Adiponectin gene expression was improved only by RES. A decrease in body weight, HOMA, liver TGs, AST/ALT ratio and TNF-α were observed in all treatment groups. Liver index was increased in FENO and FENO + RES groups. Serum TGs was improved only by FENO treatment. Liver MDA was improved by RES and FENO + RES treatments. FENO + RES group showed an increase in liver GSH content.

CONCLUSION: When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate.

Keywords: Fructose, Nonalcoholic steatohepatitis, Suppressor of cytokine signaling-3, Sterol regulatory element binding protein-1c, Fatty acid synthase, Malonyl CoA decarboxylase, Leptin, Adiponectin, Transforming growth factor-β, Tumor necrosis factor-α

Core tip: The current work may justify the use of lower doses of fenofibrate in combination with resveratrol to protect the liver from fructose induced hepatic steatosis and damage. The synergistic effect may be due to antioxidant, anti-inflammatory and anti-hyperlipidemic effect of resveratrol. As an add-on therapy, resveratrol can augment the beneficial outcome of a lower dose of fenofibrate and reduces its toxic or side effects.