Abstract
A diet-induced non-alcoholic fatty liver disease (NAFLD) model causing obesity in rodents was used to examine whether sitagliptin and gliclazide therapies have similar protective effects on pathological liver change. Methods: Male mice were fed a high-fat diet (HFD) or standard chow (Chow) ad libitum for 25 weeks and randomly allocated to oral sitagliptin or gliclazide treatment for the final 10 weeks. Fasting blood glucose and circulating insulin were measured. Inflammatory and fibrotic liver markers were assessed by qPCR. The second messenger ERK and autophagy markers were examined by Western immunoblot. F4/80, collagens and CCN2 were assessed by immunohistochemistry (IHC). Results: At termination, HFD mice were obese, hyperinsulinemic and insulin-resistant but non-diabetic. The DPP4 inhibitor sitagliptin prevented intrahepatic induction of pro-fibrotic markers collagen-IV, collagen-VI, CCN2 and TGF-β1 and pro-inflammatory markers TNF-α and IL-1β more effectively than sulfonylurea gliclazide. By IHC, liver collagen-VI and CCN2 induction by HFD were inhibited only by sitagliptin. Sitagliptin had a greater ability than gliclazide to normalise ERK-protein liver dysregulation. Conclusion: These data indicate that sitagliptin, compared with gliclazide, exhibits greater inhibition of pro-fibrotic and pro-inflammatory changes in an HFD-induced NAFLD model. Sitagliptin therapy, even in the absence of diabetes, may have specific benefits in diet-induced NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common chronic liver disease in developed countries [1]
The definition of NAFLD encompasses the entire spectrum of fatty liver disease, including simple steatosis and non-alcoholic steatohepatitis (NASH)
The high-fat diet (HFD) fed mice, as expected for this mouse strain, had normal blood glucose compared with the control group (Figure 1B)
Summary
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common chronic liver disease in developed countries [1]. The definition of NAFLD encompasses the entire spectrum of fatty liver disease, including simple steatosis and non-alcoholic steatohepatitis (NASH). NAFLD presence is estimated to be as high as 80% in obese patients, compared with 16% in individuals with normal. In obese people with NAFLD, excessive caloric intake is implicated in NAFLD development, so we adopted an established high-fat-fed mouse model to mimic these groups of patients. In a previous study of a high-fat-feeding mouse model, it was reported that after a prolonged dietary period of 20 weeks, the high-saturated-fat diet resulted in two of the three important features of NASH: lipid accumulation and leukocyte (macrophage) inflammatory infiltration, compared with chow-fed animals [7]
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