Clinical Research
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 21, 2006; 12(27): 4369-4376
Published online Jul 21, 2006. doi: 10.3748/wjg.v12.i27.4369
Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease
Nimer Assy, Masha Grozovski, Ilana Bersudsky, Sergio Szvalb, Osamah Hussein
Nimer Assy, Liver Unit, Sieff Hospital, Safed, Israel and Technion Institute, Faculty of Medicine, Haifa, Israel
Nimer Assy, Osamah Hussein, Department of Internal Medicine A, Sieff Hospital, Safed, Israel
Masha Grozovski, Ilana Bersudsky, Ort Braude College, Karmiel, Israel
Sergio Szvalb, Department of Pathology, Sieff Hospital, Safed, Israel
Correspondence to: Dr. Nimer Assy, Liver Unit, Sieff Government Hospital, POB 1008, Safed 13100, Israel. assy.n@ziv.health.gov.il
Telephone: +972-46-828943 Fax: +972-46-828944
Received: February 17, 2006
Revised: February 28, 2006
Accepted: March 10, 2006
Published online: July 21, 2006
Abstract

AIM: To assess whether treatment with insulin-sensitizing agents (ISAs) in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet (MCDD) rat model of non-alcoholic fatty liver disease (NAFLD).

METHODS: Rats (n = 6 per group) were treated with different drugs, including MCDD only, MCDD diet with either metformin (200 mg/kg), rosiglitazone (3 mg/kg), metformin plus rosiglitazone (M+R), ezetimibe (2 mg/kg), valsartan (2 mg/kg), or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured.

RESULTS: Fatty liver (FL) rats demonstrated severe hepatic fatty infiltration (> 91% fat), with an increase in hepatic TG (+1263%, P < 0.001), hepatic cholesterol (+245%, P < 0.03), hepatic MDA levels (+225%, P < 0.001), serum TNF-alpha (17.8 ± 10 vs 7.8 ± 0.0, P < 0.001), but a decrease in hepatic alpha tocopherol (-74%, P < 0.001) as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis (-54%), hepatic TG (-64%), hepatic cholesterol (-31%) and hepatic MDA (-70%), but increased hepatic alpha tocopherol (+443%) as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis (-32% vs -54%, P < 0.001) and in hepatic MDA levels (-55% vs -70%, P < 0.01), but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group.

CONCLUSION: Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.

Keywords: Fatty liver; Rosiglitazone; Metformin; Ezetimibe; Valsartan; Methionine choline-deficient diet; Insulin resistance