Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl-CoA desaturase-1, lipase activity, leptin and resistin

Abstract

Hepatosteatosis is a disease present worldwide, which presents a number of health problems. Recently, thiazolidinedione (TZD) has been used as a therapy for lipid disorders. The present study demonstrates the potential of TZD as a treatment for hepatosteatosis and its mechanism of action, particularly focusing on its role in lipid metabolism. A total of 60 (80-90 g) rats were divided into three groups: A normal group with a standard diet, a high-fat, high-carbohydrate diet (HFCD) group or a HFCD+TZD group (n=20/group). The HFCD induced hepatosteatosis over a period of 12 weeks and the HFCD+TZD group were administered TZD in weeks 13-16. Blood and tissue samples were collected to measure hepatic function, the lipid profile, metabolism and hormone biomarkers, including serum triglyceride (TG), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD-1), leptin and resistin. The HFCD-fed rats exhibited a significant increase in serum TG, total cholesterol, low-density lipoproteins, alanine transaminase and bilirubin compared with the normal group as well as a significant decrease in high-density lipoprotein. In addition, serum leptin and resistin were significantly elevated in the HFCD group compared with the normal group. The administration of TZD significantly increased SCD-1 activity and significantly inhibited LPL activity. It also attenuated the changes in the lipid profiles and normalized serum leptin and resistin levels. The results of the present study indicated that HFCD induced lipid abnormalities associated with hypertriglyceridemia, hypercholesterolemia and hepatosteatosis. These changes resulted from disruption to leptin and resistin, which may be due to alterations in LPL and SCD-1 activity. TZD mitigated the effects of HFCD-induced hepatosteatosis, indicating a possible regulatory effect of TZD in the development of hepatosteatosis. The authors suggest that the manipulation of SCD-1 and lipase by TZD may be useful as a treatment for hepatosteatosis.

Keywords: hepatosteatosis; high-carbohydrate diet; high-fat; lipase; lipid metabolism; stearoyl-CoA desaturase; thiazolidinedione.

Figure 1.

Effect of normal diet or HFCD on rat body weight gain. *P<0.05 vs. normal group. HFCD, HFCD, high-fat, high-carbohydrate diet.

Figure 2.

Effect of normal diet, HFCD and HFCD+TZD on ALT as liver function biomarker. *P<0.05 vs. normal group. ^#P<0.05 vs. HFCD group. HFCD, high-fat, high-carbohydrate diet; TZD, thiazolidinedione.

Figure 3.

Effect of normal diet, HFCD or HFCD+TZD on serum (A) TG, (B) TC, (C) LDL and (D) HDL levels. *P<0.05 vs. normal group. ^#P<0.05 vs. HFCD group. HFCD, high-fat, high-carbohydrate diet; TZD, thiazolidinedione; TG, triglycerides; TC, total cholesterol; LDL, low-density lipoprotein.

Figure 4.

Effect of normal diet, HFCD and HFCD+TZD on (A) leptin and (B) resistin hormone in rats. *P<0.05 vs. normal group. ^#P<0.05 vs. HFCD group. HFCD, high-fat, high-carbohydrate diet; TZD, thiazolidinedione.

Figure 5.

Histopathological examination of different treatment groups. Histopathological outcomes in the (A) normal, (B) HFCD and (C) HFCD+TZD treatment groups. The normal tissue samples (Aa) and (Ab) demonstrated characteristic histological configuration of ordinary hepatocytes, without inflammatory cells in the perivenular area. Several fat bubbles were observed among and inside the hepatocytes in the (Ba) and (Bb) HFCD liver tissue samples, which is associated with deteriorating alterations in the hepatocytes (magnification, ×100). The HFCD group had macrovesicular hepatosteatosis (large fat drops present in the hepatocytes, indicated by arrow a) and microvesicular steatosis (slight fat droplets in the hepatocytes, indicated with arrow b). Liver focal periportal inflammation (magnification, ×100) and accumulation (cluster) of inflammatory cells in the HFCD group indicated with arrow c. The hepatocytes appeared normalized and had a normal shape and minor lipid globules in the (Ca) and (Cb) HFCD+TZD liver tissue samples. HFCD, high-fat, high-carbohydrate diet; TZD, thiazolidinedione.