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Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase‑IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase‑IV is known to be increased in non‑alcoholic steatohepatitis. Therefore, dipeptidyl peptidase‑IV inhibitors are potential therapeutic agents for non‑alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase‑IV inhibitor, on non‑alcoholic steatohepatitis using fatty liver Shionogi‑ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi‑ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor‑β1, tissue inhibitor of metalloproteinases‑1, procollagen‑type 1, tumor necrosis factor‑α, monocyte chemoattractant protein‑1 and enhanced peroxisome proliferator activated receptor‑α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis.

The aim of this study was to examine the preventative and therapeutic effects of an angiotensin-converting enzyme inhibitor, perindopril, on cholestasis-induced liver fibrosis. Perindopril was administered orally for 21 days immediately after bile duct ligation at a dose of 2 mg/kg in order to evaluate the preventative effects, and for 21 days starting 3 weeks after bile duct ligation at doses of 2 and 8 mg/kg in order to evaluate the therapeutic effects. With regard to the preventative effects, perindopril reduced the hepatic hydroxyproline content by 33%, collagen-I mRNA by 38%, α-smooth muscle actin (α-SMA)-positive cells by 46%, α-SMA mRNA by 40%, transforming growth factor-β1 (TGF-β1) mRNA by 21% and connective tissue growth factor (CTGF) mRNA by 27%. With regard to the therapeutic effects, at 2 mg/kg perindopril had no inhibitory effects on the progression of liver fibrosis, but at 8 mg/kg, it reduced hepatic hydroxyproline contents by 63%, collagen-I mRNA by 94%, TGF-β1 mRNA by 79%, CTGF mRNA by 97% and tissue inhibitor of metalloproteinase-1 mRNA by 87%. Significant decreases in the oxidative stress markers hepatic 4-hydroxy-2-nonenal and 8-hydroxy-2-deoxyguanosine were noted for perindopril administration at 8 mg/kg, but not at 2 mg/kg. In conclusion, perindopril had preventative and therapeutic effects on cholestasis-induced liver fibrosis through the inhibition of oxidative stress and/or the activation of hepatic stellate cells, thus suggesting the possible application of perindopril as an antifibrotic drug.

Bile duct-ligated rats have been widely used as a model of cholestatic liver fibrosis. The aim of this study was to analyze the sequential expression of extracellular matrix (ECM) metabolism-related genes in these rats. We analyzed the intrahepatic messenger RNA (mRNA) expression of several ECM metabolism-related genes: transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), procollagen-α1 (collagen-I), matrix metalloproteinase (MMP)-2, MMP-13 and tissue inhibitor of metalloproteinases (TIMP)-1 on days 10, 21 and 42 after bile duct ligation (BDL). A DNA microarray was used to evaluate the expression of genes related to early fibrogenesis on day 10 following BDL; the grade of hepatic fibrosis was found to gradually progress from day 10 to 42. Collagen-I mRNA expression significantly increased from day 10 to day 42, as did TGF-β1 and CTGF mRNA. On the other hand, MMP-13 and -2 mRNA expression increased maximally from day 10 to 21, but tended to decrease by day 42. TIMP-1 mRNA expression was significant on day 21 and was sustained until day 42. The DNA microarray revealed genes significantly increased on day 10, including calgranulin B, solute carrier family 34, thymosin and tubulin, but not fibrogenesis-related cytokines or MMPs/TIMPs. In conclusion, the enhanced gene expression of collagen-I, TGF-β1, CTGF and TIMP-1 and the decreased gene expression of MMP-13 and -2 was noted on day 42 in BDL-induced liver fibrosis.