Int J Mol Sci. 2020;21(18):ijms21186836.

Effect of Fibroblast Growth Factor 21 on the Development of Atheromatous Plaque and Lipid Metabolic Profiles in an Atherosclerosis-Prone Mouse Model.

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제1저자 맹효진 · 교신저자 임수

PMID 32957703 PMC7555741 DOI 10.3390/ijms21186836 IF 4.556 내분비대사내과

소속 (2)

Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea.
Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Korea.

Abstract

Fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism. We aimed to investigate the effect of an FGF21 analogue (LY2405319) on the development of atherosclerosis and its associated parameters. ApoE^-/- mice were fed an atherogenic diet for 14 weeks and were randomly assigned to control (saline) or FGF21 (0.1 mg/kg) treatment group (n = 10/group) for 5 weeks. Plaque size in the aortic arch/valve areas and cardiovascular risk markers were evaluated in blood and tissues. The effects of FGF21 on various atherogenesis-related pathways were also assessed. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the FGF21 group than in controls after treatment. FGF21 significantly decreased body weight and glucose concentrations, and increased circulating adiponectin levels. FGF21 treatment alleviated insulin resistance and decreased circulating concentrations of triglycerides, which were significantly correlated with plaque size. FGF21 treatment reduced lipid droplets in the liver and decreased fat cell size and inflammatory cell infiltration in the abdominal visceral fat compared with the control group. The monocyte chemoattractant protein-1 levels were decreased and β-hydroxybutyrate levels were increased by FGF21 treatment. Uncoupling protein 1 expression in subcutaneous fat was greater and fat cell size in brown fat was smaller in the FGF21 group compared with controls. Administration of FGF21 showed anti-atherosclerotic effects in atherosclerosis-prone mice and exerted beneficial effects on critical atherosclerosis pathways. Improvements in inflammation and insulin resistance seem to be mechanisms involved in the mitigation of atherosclerosis by FGF21 therapy.

Keywords

atherosclerosisdiabetes mellitusfibroblast growth factor 21inflammation

Figures

**Figure 1** (A) Weight changes during the 5 weeks of treatment. (B) Glucose levels measured at 0–120 min during the intraperitoneal glucose tolerance test (IPGTT) at the end of study. (C–E) Fasting glucose and insulin concentrations after 5 weeks of treatment with normal saline or the fibroblast growth factor 21 (FGF21) analogue LY2405319. (E) Homeostasis model assessment of insulin resistance (HOMA-IR) calculated from fasting glucose and insulin levels. Data are means ± standard deviation (SD). * p < 0.05 vs. control.

**Figure 2** Changes in lipid profiles after 5 weeks of treatment with normal saline as control and fibroblast growth factor 21 (FGF21; 0.1 mg/kg) in the ApoE^−/− mice. (A). total cholesterol, (B). triglyceride, (C). HDL-cholesterol, (D). LDL/VLDL. * p < 0.05 vs. control.

**Figure 3** Changes in FGF21 (A), adiponectin (B), β-hydroxybutyrate (C), glucagon (D), monocyte chemoattractant protein-1 (MCP1) (E), and resistin (F) levels after 5 weeks of treatment with normal saline as a control and fibroblast growth factor 21 (FGF21; 0.1 mg/kg) in ApoE^−/− mice. Data are means ± SD. * p < 0.05 vs. control.

**Figure 4** Atheroma burden in the aorta of ApoE^−/− mice after 5 weeks of treatment with FGF21 or normal saline. (A,C) Representative images of atheroma stained using Oil Red O of the aortic arch (A) and aortic valve areas (scale bars, 100 μm) (C) from ApoE^−/− mice. The red color indicates plaque accumulation. (B,D) The atheromatous plaque area (% of total area) was smaller in the aortic arch (B) and aortic valve (D) of the FGF21-treated mice compared with the control. Data are means ± SD. Weight-adjusted comparison was used. * p < 0.05 vs. control.

**Figure 5** (A) Histology of abdominal visceral adipose tissues stained with H&E (scale bars, 20 μm). The arrows indicate crown-like structures. (B) Comparison of fat cell size (% of control) between the control and the FGF21 groups. (C) Immunohistochemical staining of CD68 in the abdominal visceral adipose tissue (scale bars, 20 μm). (D) CD68-positive cells were significantly less abundant in the FGF21-treated mice than in the controls (% of total cells). Data are means ± SD. * p < 0.05 vs. control.

**Figure 6** (A) Histology of abdominal subcutaneous adipose tissues stained with H&E (scale bars, 20 μm). Arrows indicate uncoupling protein 1 (UCP1)-positive cells. (B) UCP1-positive cells were significantly more abundant in the FGF21-treated mice than in the control (% of total cells). (C) Histology of brown adipose tissues stained by H&E (scale bars, 20 μm). (D) Comparison of fat cell size (% of control) between the control and the FGF21 group. Data are means ± SD. * p < 0.05 vs. control.

**Figure 7** (A) Liver histology revealed by H&E staining. All images were acquired at magnification x 200 (n = 10 in the control, n = 9 in the FGF21 group). (B) Triglyceride content in the liver (mmol/g). Data are means ± SD. * p < 0.05 vs. control.

그림 출처: PubMed Central 공개 논문 (PMC7555741)

Conflict of interest statement

The authors declare no conflict of interest.

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