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


CONCLUSIONS
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.
Assy
Nimer
N
Liver Unit, Sieff Government Hospital, POB 1008, Safed 13100, Israel. assy.n@ziv.health.gov.il
Grozovski
Masha
M
Bersudsky
Ilana
I
Szvalb
Sergio
S
Hussein
Osamah
O
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005223:Fats / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
D000924:Anticholesteremic Agents; D001384:Azetidines; D005223:Fats; D007004:Hypoglycemic Agents; D013777:Tetrazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D000068756:Valsartan; D008687:Metformin; D000069438:Ezetimibe; D014633:Valine