Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

AIM： To assess whether treatment with insulinsensitizing 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.

Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats

AIM： To evaluate the effects of different types of dietary fats on the hepatic lipid content and oxidative stress parameters in rat liver with experimental non-alcoholic fatty liver disease （NAFLD）. METHODS： A total of 32 Sprague-Dawley rats were randomly divided into five groups. The rats in the control group （n = 8） were on chow diet （Group 1）, rats （n = 6） on methionine choline-deficient diet （MCDD） （Group 2）, rats （n = 6） on MCDD enriched with olive oil （Group 3）, rats （n = 6） on MCDD with fish oil （Group 4） and rats （n = 6） on MCDD with butter fat （Group 5）. After 2 mo, blood and liver sections were examined for lipids composition and oxidative stress parameters. RESULTS： The liver weight/rat weight ratio increased in all treatment groups as compared with the control group. Severe fatty liver was seen in MCDD ＋ fish oil and in MCDD ＋ butter fat groups, but not in MCDD and MCDD ＋ olive oil groups. The increase in hepatic triglycerides （TG） levels was blunted by 30% in MCDD ＋ olive oil group （0.59 ±0.09） compared with MCDD group （0.85 ±0.04, P 〈 0.004）, by 37% compared with MCDD ＋ fish oil group （0.95 ±0.07, P 〈 0.001）, and by 33% compared with MCDD ＋ butter group （0.09 ±0.1, P 〈 0.01）. The increase in serum TG was lowered by 10% in MCDD ＋ olive oil group （0.9 ±0.07） compared with MCDD group （1.05 ±0.06）. Hepatic cholesterol increased by 15-fold in MCDD group [（0.08 ±0.02, this increment was blunted by 21% in MCDD ＋ fish oil group （0.09 ±0.02）]. In comparison with the control group, ratio of long-chain polyunsaturated fatty acids omega-6/omega-3 increased in MCDD ＋ olive oil, MCDD ＋ fish oil and MCDD ＋ butter fat groups by 345-, 30- and 397-fold, respectively. In comparison to MCDD group （1.58 ±0.08）, hepatic MDA contents in MCDD ＋ olive oil （3.3 ±0.6）, MCDD ＋ fish oil （3.0 ±0.4）, and MCDD ＋ butter group （2.9 ±0.36） were increased by 108%, 91% and 87%, respectively （P 〈 0.004）. Hepatic paraoxonase activity decreased significantly in all treatment groups, mostly with MCDD ＋ olive oil group （-68%）.CONCLUSION： Olive oil decreases the accumulation of triglyceride in the liver of rats with NAFLD, but does not provide the greatest antioxidant activity.