Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Abstract

Abstract. 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. IntroductionNon-alcoholic steatohepatitis (NASH) is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The central pathophysiological issue in patients afflicted with NASH is insulin resistance. Improvement of insulin resistance has therapeutic potential in preventing the progression of NASH (1). Previously, dipeptidyl peptidase (DPP)-IV inhibitors have been used as novel oral drugs for the treatment of type 2 diabetes. DPP-IV is an enzyme, which inactivates incretins, including glucagon-like peptide-1 and gastric inhibitory polypeptide, which regulates blood glucose primarily via stimulation of glucose-dependent insulin release. As a result, the activation of DPP-IV leads to the development of glucose intolerance and hepatic steatosis (2). DPP-IV enzyme has widespread organ distribution throughout the body and has pleiotropic biological functions (3-5). DPP-IV is involved in glucose metabolism and lipid accumulation, degradation of the extracellular matrix, appetite regulation and immune stimulation via its peptidase activities (6-10). The liver is one of the organs expressing DPP-IV to a high degree (11). The mRNA expression of DPP-IV is also increased in the liver of non-alcoholic fatty liver disease (NAFLD) (12). Serum DPP-IV activity and the expression of hepatic DPP-IV are correlated with hepatic steatosis and NAFLD s...

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

“…The oxidative damage induced by MTX in liver tissue was prevented by sitagliptin pretreatment as it provided anti-oxidant effects not only on the non-enzymatic defense system (GSH), but also on the enzymatic one such as SOD. Similar antioxidant effects of sitagliptin were recently reported in many inflammatory conditions including myocardial injury [12,21], liver steatohepatitis [13,14], type 2 diabetes [22] and renal ischemia/reperfusion injury [23]. …”

“…Recently, the anti-inflammatory action of sitagliptin has been reported in different types of cardiovascular injury [10–12]. Notably, sitagliptin has shown hepatoprotective activity in experimentally induced steatohepatitis via modulation of lipid metabolism, oxidative stress and inflammatory mediators [13,14]. However, the exact mechanism of its hepatoprotective activity is complex and not completely clarified.…”

Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats

“…These results are in accordance with the previous studies which showed the ability of sitagliptin to reduce the oxidative burden in different experimental models of organs toxicities. 22,28,42,43 In addition to its direct toxic effects, ROS can induce nuclear transcription factor-kB (NF-kB) activation which leads to its translocation into the nucleus where it binds to the promoter elements and activate the expression of inflammatory cytokine genes with subsequent proinflammatory mediators production such as TNF-a, COX-2, and NO. 7,44 In the current study, DOX administration resulted in the increased expression of NF-kB as well as increased levels of TNF-a and NO.…”

Sitagliptin in Patients with Non-Alcoholic Steatohepatitis: A Randomized, Placebo-Controlled Trial

“…In rodent models, sitagliptin use has resulted in improved features of NASH [20,37,38] . In humans, randomized controlled trials examining the effect of sitagliptin on liver histology has not previously been examined.…”

“…Thus, DPP-IV itself may be important to the pathogenesis of NASH. Use of the DPP-IV inhibitor, sitagliptin, improves lipid metabolism, and attenuates the progression of hepatic fibrosis in mice with NASH, as well as decreases platelet aggregation in vitro [20,21] . Thus, sitagliptin may be an attractive therapeutic option for NASH, especially given its low risk of hypoglycemia, weight-neutrality, and demonstrated safety profile in individuals with moderate hepatic insufficiency [22,23] .…”