Rosiglitazone prevents fatty liver via attenuating SREBP-1 and chREBP in diabetic animal model

Abstract

The imbalance of high-caloric intake and fat accumulation in liver cause abnormally increased expression of nuclear SREBPs and ChREBP which play a major role in lipid and glucose homeostasis. Diabetic animals treated with high-calorie diet were known to increase lipogenesis associated with SREBP-1 and ChREBP. Rosiglitazone strongly regulates lipid storage in adipose tissue. This study aimed to find whether rosiglitazone protect fatty liver in diabetic animals with regards to SREBPs and ChREBP. OLETF rats were divided into three groups: control group (C, normal chow diet, N=8), high-fat diet group (HF, 40% lard oil, N=8), and high-fat diet treated with rosiglitazone group (HR, 4 mg/Kg rosiglitazone and 40% lard oil, N=8). Rats in HF and HR group showed no differences in body weight after 3-week treatment. Although fasting plasma glucose levels were similar in each group, the glucose tolerance was improved in rosiglitaszone-treated rats compared to that in vehicle-treated rats. Rosiglitazone treatment lowered the concentrations of triglycerides (0.79 ± 0.60 vs 1.27 ± 0.28 mmol/L, p<0.05) and total cholesterol (2.78 ± 0.06 vs 3.57 ± 0.34 mmol/L) in the plasma compared to those in vehicle-treated group. Histological examination showed significant reduction of filipin positive free cholesterol and oil-red O positive lipid deposition in liver of rosiglitazone treated group. The measurement of hepatic TG showed the same trend with plasma level (A.U HR: 10.45 ± 0.7 vs HF: 11.47 ± 0.11, p<0.01). In addition, rosiglitazone treatment attenuated expression of nuclear SREBP-1, SREBP-2 and ChREBP. The amount of SREBP-1, SREBP-2 and ChREBP proteins in nuclei of hepatocytes were increased in HF group compared to C group, however, significantly decreased in HR group than HF group. The expression of mRNA for SREBP-1 and ChREBP correlated the changes in their proteins, however the expression of mRNA for SREBP-2 remained same at transcriptional level. These results suggest that rosiglitazone reduces lipid accumulation in liver by decreasing the expression of SREBP-1 and ChREBP, resulting in protecting liver from fatty liver developing in diabetic animal models.