The Effect of Sitagliptin on Lipid Metabolism of Fatty Liver Mice and Related Mechanisms.
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.
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Bilin
B
Xu
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Tian
T
Shen
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Lin
L
Chen
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Juan
J
Xia
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Cuiping
C
Zhang
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Hongping
H
Wang
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Ming
M
Yu
Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland).
Tao
T
Lei
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000097:blood / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000097:blood / Q000378:metabolism; D000068900:Sitagliptin Phosphate / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*
C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047493:PPAR alpha; D005346:Fibroblast Growth Factors; D002334:Carnitine O-Palmitoyltransferase; D000068900:Sitagliptin Phosphate