The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet

Abstract

Objective-Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation.Methods-Male Sprague-Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry.Results-Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1β in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and

High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats

“…Sitagliptin is reported to cause delay in gastric emptying, increase in insulin sensitivity and produce anti-oxidative and anti-inflammatory effects (which are independent of hypoglycemic effects) [33,34]. Therefore, the increase in hepatic oxidative stress by sitagliptin in rats fed the high Cho diet was unexpected and similar to our recent findings where sitagliptin increased the hepatic inflammation in hypercholesterolemic rats [51]. In support of our findings of the harmful effects of sitagliptin in high Cho fed animals, there are reports of sitagliptin causing cardiac [52], hepatic [53,54] and pancreatic damage [55].…”

Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats

“…The observed responses were independent of body composition, body weight and blood glucose levels, which were similar among dietary groups. Cardiac responses seen at this point appear to coincide with our hepatic studies, in that Cho feeding (alone) resulted in adverse effects [33,34].…”

“…The underlying mechanisms for the relationship between NAFLD and CVD are believed to be incompletely understood; however, in ammation, endothelial dysfunction, and dyslipidemia are positioned as signi cant factors [32]. Our lab previously observed hepatic in ammatory and oxidative stress responses in HChol, an observation that was exacerbated by sitagliptin administration [33,34]. Sitagliptin (Januvia) is a type 2 diabetic drug currently in clinical use for the management of hyperglycemia, via dipeptidyl peptidase-4 (DPP-4) inhibition [35].…”

Effects and Safety of Sitagliptin in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

“…In addition, experimental studies achieved more typical and severe NAFLD models, which might lead to more treatment efficacy. Strikingly, a recent animal studies revealed the hepato-inflammatory effects of sitagliptin, which sitagliptin exacerbates the expression of hepatic inflammatory markers accompanied by hepatic necrosis and mononuclear cell infiltration in high-cholesterol dieted rats [26]. As known, cholesterol is an important risk factor in NAFLD pathogenesis.…”

“…Therefore, there seem to be plausible mechanisms that DPP-4-inhibitors might have beneficial effects in NAFLD treatment. Recent studies have demonstrated the controversial effect of sitagliptin on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic steatosis in experimental models [24][25][26]. In human trails, some nonrandomized controlled trials (non-RCTs) with human subjects showed sitagliptin improved liver function in NAFLD patients [27][28][29][30][31].…”