The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet
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.
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.
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 mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells.
When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.
KeywordsDPP-4 inhibitor Hepatic necrosis Hypercholesterolemia Inflammation
The funding support from the Louisiana Biomedical Research Network is gratefully acknowledged. We thank the services provided by the Cell Biology and Bioimaging Core at Pennington Biomedical Research Center.
SNM conceived, designed and conducted the study; TWG provided valuable support in conducting and supervising the study; RP, AK and HAP conducted all the animal experiments. RP and AK performed all the biochemical analysis and analyzed data; SNM, RP and AK wrote the paper; TWG revised the manuscript; LAF and KPS helped in reviewing and provided useful suggestions; NRR, a board-certified pathologist evaluated and provided histopathological scoring for liver specimens and also contributed to the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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