SCI 발표논문

SCI 발표논문

← SCI 발표논문 목록

Endocrinol Metab (Seoul). 2021;36(1):157-170.

Effects of Glucagon-Like Peptide-1 Analogue and Fibroblast Growth Factor 21 Combination on the Atherosclerosis-Related Process in a Type 2 Diabetes Mouse Model.

, , , , , ,

제1저자 김진희 · 교신저자 임수

PMID 33677937 PMC7937856 DOI 10.3803/EnM.2020.781 IF 5.1 내분비대사내과
소속 (2)
  1. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
  2. Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND Glucagon-like peptide-1 (GLP-1) analogues regulate glucose homeostasis and have anti-inflammatory properties, but cause gastrointestinal side effects. The fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism that has poor pharmacokinetic properties, including a short half-life. To overcome these limitations, we investigated the effect of a low-dose combination of a GLP-1 analogue and FGF21 on atherosclerosis-related molecular pathways.

METHODS C57BL/6J mice were fed a high-fat diet for 30 weeks followed by an atherogenic diet for 10 weeks and were divided into four groups: control (saline), liraglutide (0.3 mg/kg/day), FGF21 (5 mg/kg/day), and low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day) (n=6/group) for 6 weeks. The effects of each treatment on various atherogenesisrelated pathways were assessed.

RESULTS Liraglutide, FGF21, and their low-dose combination significantly reduced atheromatous plaque in aorta, decreased weight, glucose, and leptin levels, and increased adiponectin levels. The combination treatment upregulated the hepatic uncoupling protein-1 (UCP1) and Akt1 mRNAs compared with controls. Matric mentalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were downregulated and phosphorylated Akt (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-ERK) were upregulated in liver of the liraglutide-alone and combination-treatment groups. The combination therapy also significantly decreased the proliferation of vascular smooth muscle cells. Caspase-3 was increased, whereas MMP-9, ICAM-1, p-Akt, and p-ERK1/2 were downregulated in the liraglutide-alone and combination-treatment groups.

CONCLUSION Administration of a low-dose GLP-1 analogue and FGF21 combination exerts beneficial effects on critical pathways related to atherosclerosis, suggesting the synergism of the two compounds.

Keywords

AtherosclerosisDiabetes mellitusFibroblast growth factor 21Glucagon-like peptide 1Inflammation

Figures

Fig. 1
Fig. 1 Atheroma burden in the aorta of C57BL/6J mice after 6 weeks of treatment with liraglutide (0.3 mg/kg/day), fibroblast growth factor 21 (FGF21; 5 mg/kg/day), and a low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day) (n=6 in each group). (A) Representative images of atheromata in the aorta stained with Oil-Red-O (scale bar, 0.5 cm). The red color indicates plaque accumulation. (B) The atheromatous plaque area (% of total area) in the aorta. Data are mean±standard deviation. aP<0.05 vs. control; bP<0.05 vs. liraglutide (0.3 mg/kg); cP<0.05 vs. FGF21 (5 mg/kg).
Fig. 2
Fig. 2 Effect of a 6-week treatment with liraglutide (0.3 mg/kg/day) alone, fibroblast growth factor 21 (FGF21; 5 mg/kg/day) alone, and liraglutide (0.1 mg/kg/day) plus FGF21 (2.5 mg/kg/day) low-dose combination therapy on (A) body weight, (B) blood glucose concentrations, and (C) food intake. Post hoc analysis by least significant difference t tests of the mean differences between two groups. aControl vs. liraglutide (0.3 mg/kg/day); bControl vs. FGF21 (5 mg/kg/day); cControl vs. low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day); dFGF21 (5 mg/kg/day) vs. liraglutide (0.3 mg/kg/day); eFGF21 (5 mg/kg/day) vs. low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day), n=6 in each group, P<0.05 in all cases.
Fig. 3
Fig. 3 Effect of liraglutide and fibroblast growth factor 21 (FGF21) on the circulating concentrations of biomarkers. (A) Insulin, (B) glucagon, (C) adiponectin, (D) leptin, (E) ghrelin, and (F) resistin concentrations were measured after 6 weeks of treatment (mean±standard error). aControl vs. liraglutide (0.3 mg/kg/day); bControl vs. FGF21 (5 mg/kg/day); cControl vs. low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day), n=6 in each group, P<0.05 in all cases.
Fig. 4
Fig. 4 Effect of liraglutide alone and the liraglutide and fibroblast growth factor 21 (FGF21) combination on inflammation, adhesion molecules, phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated kinase (p-ERK), and uncoupling protein-1 (UCP1) in the liver and p-Akt, p-ERK in visceral fat. (A) The expression of matric mentalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in mouse liver was decreased after treatment with liraglutide and the liraglutide and FGF21 combination. (B, C) In the liver and visceral fat, treatment with liraglutide or the liraglutide and FGF21 combination increased the levels of p-Akt and p-ERK compared with control animals. (D) Relative expression of the UCP1 and Akt1 mRNA in the mouse liver, as analyzed by quantitative polymerase chain reaction (mean±standard error). aP<0.05.
Fig. 5
Fig. 5 Liraglutide alone or in combination with fibroblast growth factor 21 (FGF21) inhibits cell proliferation, and migration. (A) A 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was performed to determine vascular smooth muscle cell (VSMC) viability. VSMCs were exposed to the indicated concentrations of liraglutide or combination treatment for 24 hours, followed by treatment with or without platelet-derived growth factor (PDGF; 10 ng/mL). (B) Quantification of the wound area. The effect of a 24-hour treatment with liraglutide or the liraglutide and FGF21 combination on the migration of VSMCs was determined by an in vitro scratch wound-healing migration assay. Each experiment was performed in triplicate (mean±standard error). aP<0.05.
Fig. 6
Fig. 6 Effect of liraglutide and fibroblast growth factor 21 (FGF21) on vascular smooth muscle cell (VSMC) apoptosis. (A) Flow cytometry analysis of fluorescein isothiocyanate (FITC)/Annexin V- and propidium iodide-stained VSMCs treated with liraglutide alone (50 μM) or combination of liraglutide (10 μM) and FGF21 (50 nM) for 24 hours. In each scatter plot, the upper-left quadrant shows necrotic cells, the upper-right quadrant shows late apoptotic cells, the lower-left quadrant shows the survival cell mass, and the lower-right quadrant shows early apoptotic cells. (B) Representative three sets of Western blotting bands showing the upregulation of cleaved caspase-3 by liraglutide alone (50 μM) or combination of liraglutide (10 μM) and FGF21 (50 nM) treatment. An anti-cleaved caspase-3 (Asp175) monoclonal antibody was used to detect the large fragment (17/19 kDa) of activated caspase-3 resulting from cleavage adjacent to Asp175. Each experiment was performed in triplicate (mean±standard error). PDGF, platelet-derived growth factor. aP<0.05.
Fig. 7
Fig. 7 Effect of liraglutide alone and the liraglutide and fibroblast growth factor 21 (FGF21) combination on inflammation, adhesion molecules, and Akt and extracellular signal-regulated kinase (ERK)1/2 in vascular smooth muscle cells (VSMCs). (A) The decrease in matric mentalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) expression in VSMCs was more pronounced in cells treated with liraglutide and the combination treatment compared with the platelet-derived growth factor (PDGF)-stimulated group. (B) Liraglutide alone and the liraglutide and FGF21 combination treatment significantly suppressed the PDGF-induced phosphorylation of Akt and ERK in VSMCs (mean±standard error). aP<0.05.

그림 출처: PubMed Central 공개 논문 (PMC7937856)

Comment · 정정

Conflict of interest statement

CONFLICTS OF INTEREST. No potential conflict of interest relevant to this article was reported.

그 밖의 정보
출판 형태
Journal Article, Research Support, Non-U.S. Gov't
저널
Endocrinology and metabolism (Seoul, Korea) · eISSN 2093-5978
전자 출판
2021-02-24
MeSH
Animals · Atherosclerosis* / drug therapy · Diabetes Mellitus, Type 2* / drug therapy · Fibroblast Growth Factors · Glucagon-Like Peptide 1 / therapeutic use · Mice · Mice, Inbred C57BL
Substances
fibroblast growth factor 21 · Fibroblast Growth Factors · Glucagon-Like Peptide 1
참고문헌
55편