The Effect of Sitagliptin on Lipid Metabolism of Fatty Liver Mice and Related Mechanisms

Abstract

BACKGROUND In clinics, patients with type 2 diabetes complicated with non-alcoholic fatty liver disease (NAFLD) have been shown to receive significant improvements in blood glucose levels, lipid levels, and liver function after sitagliptin treatment, although the mechanism of drug action remains poorly understood. This study investigated the possible mechanism of sitagliptin on lipid metabolism of NAFLD mice. MATERIAL AND METHODS Male C57/BL6 mice were induced for NAFLD via 16 weeks of a high-fat diet, and were treated with 15 mg/kg/day sitagliptin for 16 consecutive weeks. Blood lipid levels were measured and samples were stained with hematoxylin and eosin (H&E) and oil red staining for liver pathology and lipid deposition. Serum levels of fibroblast growth factor (FGF)-9 and FGF-21 were quantified by enzyme-linked immunosorbent assay (ELISA). Peroxisome proliferator-activated receptor (PPAR)-α, and cAMP reactive element binding homolog (CREBH) were measured by Western blotting, while fatty acid synthase and carnitine palmitoyltransferase 1 (CPT1) mRNA levels were assayed by RT-PCR. RESULTS Compared to the control group, the NAFLD model mice had liver fatty disease, lower serum FGF-21 and FGF-19 levels, elevated serum lipid levels, depressed PPAR-α, CREBH, and CPT1 expression, and enhanced FAS expression (p<0.05). Sitagliptin treatment depressed blood lipid levels, increased serum FGF-21 and FGF-19 levels, PPAR-α, CREBH, and CPT1 expression, and suppressed FAS expression (p<0.05). CONCLUSIONS Sitagliptin can protect liver tissue and modulate lipid metabolism in NAFLD mice via elevating FGF-21 and FGF-19, upregulating liver PPAR-a and CREBH levels, and mediating expression levels of key enzymes for lipid metabolism.

Figure 1

The effect of sitagliptin on body weight of NAFLD mice. A – Control group; B – Model group; C – Sitagliptin group. * p<0.05 compared to control group; ^# p<0.05 compared to model group.

Figure 2

(A–D) Effect of sitagliptin on blood lipid and liver function in NAFLD mice. A – Control group; B – Model group; C – Sitagliptin group. * p<0.05 compared to control group; ^# p<0.05 compared to model group.

Figure 3

Hepatic morphology of NAFLD mice after sitagliptin treatment.

Figure 4

Hepatic lipid disease grade of all groups. A – Control group; B – Model group; C – Sitagliptin group. * p<0.05 compared to control group; ^# p<0.05 compared to model group.

Figure 5

Effect of sitagliptin on FGF-19 (A) and FGF-21 (B) levels in mice. A – Control group; B – Model group; C – Sitagliptin group. * p<0.05 compared to control group; ^# p<0.05 compared to model group.

Figure 6

(A, B) FAS and CPT1 mRNA expression levels in mice hepatic tissues. A – Control group; B – Model group; C – Sitagliptin group. * p<0.05 compared to control group; ^# p<0.05 compared to model group.

Figure 7

Expression level of PRAR-α and CREBH in mice hepatic tissues. A – Control group; B – Model group; C – Sitagliptin group. * p<0.05 compared to control group; ^# p<0.05 compared to model group.