Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice

Abstract

Aims/introduction: Dipeptidyl peptidase-4 inhibitors are used for treatment of patients with type 2 diabetes. In addition to glycemic control, these agents showed beneficial effects on lipid metabolism in clinical trials. However, the mechanism underlying the lipid-lowering effect of dipeptidyl peptidase-4 inhibitors remains unclear. Here, we investigated the lipid-lowering efficacy of anagliptin in a hyperlipidemic animal model, and examined the mechanism of action.

Materials and methods: Male low-density lipoprotein receptor-deficient mice were administered 0.3% anagliptin in their diet. Plasma lipid levels were assayed and lipoprotein profile was analyzed using high-performance liquid chromatography. Hepatic gene expression was examined by deoxyribonucleic acid microarray and quantitative polymerase chain reaction analyses. Sterol regulatory element-binding protein transactivation assay was carried out in vitro.

Results: Anagliptin treatment significantly decreased the plasma total cholesterol (14% reduction, P < 0.01) and triglyceride levels (27% reduction, P < 0.01). Both low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol were also decreased significantly by anagliptin treatment. Sterol regulatory element-binding protein-2 messenger ribonucleic acid expression level was significantly decreased at night in anagliptin-treated mice (15% reduction, P < 0.05). Anagliptin significantly suppressed sterol regulatory element-binding protein activity in HepG2 cells (21% decrease, P < 0.001).

Conclusions: The results presented here showed that the dipeptidyl peptidase-4 inhibitor, anagliptin, exhibited a lipid-lowering effect in a hyperlipidemic animal model, and suggested that the downregulation of hepatic lipid synthesis was involved in the effect. Anagliptin might have beneficial effects on lipid metabolism in addition to a glucose-lowering effect.

Keywords: Anagliptin; Dipeptidyl peptidase-4 inhibitor; Lipid metabolism.

Figure 1

Lipid‐lowering effects of dipeptidyl peptidase‐4 inhibitors in low‐density lipoprotein receptor‐deficient mice with anagliptin (Ana). (a) Bodyweight (BW). Plasma concentrations of (b) total cholesterol (TC) and (c) triglyceride (TG) after 4 weeks of treatment. Data are shown as mean ± standard error of the mean (n = 10). **P < 0.01.

Figure 2

Lipid profiling by high‐performance liquid chromatography in low‐density lipoprotein receptor‐deficient mice with anagliptin (Ana). Plasma (a) very low‐density lipoprotein cholesterol (VLDL‐C), (b) low‐density lipoprotein cholesterol (LDL‐C) and (c) high‐density lipoprotein cholesterol (HDL‐C) concentrations after 4 weeks of anagliptin treatment. Data are shown as mean ± standard error of the mean (n = 10). *P < 0.05.

Figure 3

Hepatic gene expression in low‐density lipoprotein receptor‐deficient mice after anagliptin (Ana) treatment. Hepatic (a) sterol regulatory element‐binding protein (SREBP)‐1c and (b) SREBP‐2 expression levels at night. Data are shown as mean ± standard error of the mean (n = 10), *P < 0.05. mRNA, messenger ribonucleic acid.

Figure 4

Sterol regulatory element‐binding protein (SREBP) transactivation assay in vitro. HepG2 cells transfected with luciferase vector with SRE were incubated with anagliptin at various concentrations (0.001–10 μmol/L) in medium containing 5% lipoprotein‐deficient serum (LPDS). Data are shown as mean ± standard error of the mean. **P < 0.01, ***P < 0.001 vs control group by Dunnett's test (n = 4). FCS, fetal calf serum.