title: Ezetimibe stimulates intestinal glucagon-like peptide 1 secretion via the MEK/ERK pathway rather than dipeptidyl peptidase 4 inhibition.
abstract: 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.
  
  
  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 enteroendocrine 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.affiliation: Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kim
authors.affiliation: Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Mook
authors.initials: JM
authors.lastname: Choi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Rhee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Won-Young
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dong Il
authors.initials: DI
authors.lastname: Park
authors.affiliation: Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: cydoctor@chol.com.
authors.forename: Cheol-Young
authors.initials: CY
authors.lastname: Park
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D000069438:Ezetimibe; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism*; D007739:L Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms
chemical_list: D001384:Azetidines; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D000069438:Ezetimibe
keywords: DPP-4; ERK; Ezetimibe; GLP-1; MEK