Ezetimibe Stimulates Intestinal Glucagon-Like Peptide 1 Secretion Via the MEK/ERK Pathway Rather Than Dipeptidyl Peptidase 4 Inhibition

被引：21

作者：

Chang, Eugene ^{[1
]}

Kim, Lisa ^{[2
]}

Choi, Jung Mook ^{[2
]}

Park, Se Eun ^{[3
]}

Rhee, Eun-Jung ^{[3
]}

Lee, Won-Young ^{[3
]}

Oh, Ki-Won ^{[3
]}

Park, Sung-Woo ^{[3
]}

Park, Dong Il ^{[4
]}

Park, Cheol-Young ^{[2
,3
]}

机构：

[1] Ewha Womans Univ, Dept Nutr Sci & Food Management, Seoul, South Korea

[2] Sungkyunkwan Univ, Kangbuk Samsung Hosp, Sch Med, Diabet Res Inst, Seoul 110746, South Korea

[3] Sungkyunkwan Univ, Kangbuk Samsung Hosp, Sch Med, Dept Internal Med,Div Endocrinol & Metab, Seoul 110746, South Korea

[4] Sungkyunkwan Univ, Kangbuk Samsung Hosp, Sch Med, Dept Internal Med, Seoul 110746, South Korea

来源：

METABOLISM-CLINICAL AND EXPERIMENTAL | 2015年 / 64卷 / 05期

关键词：

Ezetimibe; GLP-1; DPP-4; ERK; MEK; DEPENDENT INSULINOTROPIC POLYPEPTIDE; TYPE-2; DIABETES-MELLITUS; HIGH-FAT DIET; CHOLESTEROL ABSORPTION INHIBITOR; PRIMARY HYPERCHOLESTEROLEMIA; GLYCEMIC CONTROL; SYNTHETIC EXENDIN-4; METABOLIC SYNDROME; GLUCOSE-TOLERANCE; INCRETIN HORMONES;

D O I：

10.1016/j.metabol.2015.02.001

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：633 / 641

页数：9

共 52 条

[51] Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes:: a parallel-group study [J].