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Ezetimibe Stimulates Intestinal Glucagon-Like Peptide 1 Secretion Via the MEK/ERK Pathway Rather Than Dipeptidyl Peptidase 4 Inhibition
- Ezetimibe Stimulates Intestinal Glucagon-Like Peptide 1 Secretion Via the MEK/ERK Pathway Rather Than Dipeptidyl Peptidase 4 Inhibition
- Chang, Eugene; Kim, Lisa; Choi, Jung Mook; Park, Se Eun; Rhee, Eun-Jung; Lee, Won-Young; Oh, Ki-Won; Park, Sung-Woo; Park, Dong Il; Park, Cheol-Young
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- METABOLISM-CLINICAL AND EXPERIMENTAL
- METABOLISM-CLINICAL AND EXPERIMENTAL vol. 64, no. 5, pp. 633 - 641
- Ezetimibe; GLP-1; DPP-4; ERK; MEK
- W B SAUNDERS CO-ELSEVIER INC
- SCI; SCIE; SCOPUS
- Document Type
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- Objective. Ezetimibe is known as a Niemann-Pick C1-Like 1 (NPC1L1) inhibitor and has been used as an agent for hypercholesterolemia. In our previous study, ezetimibe administration improved glycemic control and increased glucagon like peptide-1 (GLP-1), an incretin hormone with anti-diabetic properties. However, the mechanisms by which ezetimibe stimulates GLP-1 secretion are not fully understood. Thus, the specific aim of this study was to investigate the mechanism(s) by which ezetimibe stimulates GLP-1 secretion. Materials/methods. Male KK/H1J mice were divided into following groups: AIN-93G (NC), NC with ezetimibe (10 mg/kg/day), 45% high fat (HF) diet, and HF diet with ezetimibe. To investigate the role of ezetimibe in glucose homeostasis and GLP-1 secretion, an insulin tolerance test was performed and serum and intestinal GLP-1 levels and intestinal mRNA expression involved in GLP-1 synthesis were measured after 6 weeks of ezetimibe treatment. In vivo and in vitro dipeptidyl peptidase-4 (DPP-4) inhibition assays were employed to demonstrate the association between ezetimibe-induced GLP-1 change and DPP-4. The molecular mechanism by which ezetimibe affects GLP-1 secretion was evaluated by using human enteroendoctine NCI-H716 cells. Results. Ezetimibe supplementation significantly ameliorated HF-increased glucose and insulin resistance in the type 2 diabetic KK/H1J mouse model. Serum and intestinal active GLP-1 levels were significantly increased by ezetimibe in HF-fed animals. However, mRNA expression of genes involved in intestinal GLP-1 synthesis was not altered. Furthermore, ezetimibe did not inhibit the activity of either in vivo or in vitro dipeptidyl peptidase-4 (DPP-4). The direct effects of ezetimibe on GLP-1 secretion and L cell secretory mechanisms were examined in human NCI-H716 intestinal cells. Ezetimibe significantly stimulated active GLP-1 secretion, which was accompanied by the activation of mitogen-activated Protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Ezetimibe-increased GLP-1 secretion was abrogated by inhibiting the MEK/ERK pathway with PD98059. Conclusion. These findings suggest a possible novel biological role of ezetimibe in glycemic control to stimulate intestinal GLP-1 secretion via the MEK/ERK signaling pathway. (C) 2015 Published by Elsevier Inc.
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