Isoliquiritigenin Attenuates Atherogenesis in Apolipoprotein E-Deficient Mice.

Fen Du,Quzhen Gesang,Dongfang Wu,Hong Yu,Jia Cao,Mei Qian,Li Ma

doi:10.3390/ijms17111932

Abstract

Isoliquiritigenin (ISL) exhibits antioxidation and anti-inflammation activity. We sought to investigate the effects and mechanism of ISL on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE−/−) mice. Firstly, we determined that ISL reduced the mRNA levels of inflammatory factors interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and monocyte chemotactic protein-1 (MCP-1), while it increased the expression of several lipoprotein-related genes in peritoneal macrophages treated with lipopolysaccharide (LPS). ISL also enhanced peroxisome proliferator-activated receptor gamma (PPARγ) protein levels and reversed the changes of ATP-binding cassette transporter A (ABCA1) and cluster of differentiation 36 (CD36) in macrophages treated with oxidative low-density lipoprotein (ox-LDL). Then, in an in vivo study, female apoE−/− mice were fed a Western diet with ISL (0, 20, 100 mg/kg/day) added for 12 weeks. We found that ISL decreased the plasma cholesterol levels of very low-density lipoprotein (VLDL)/LDL, promoted plasma superoxide dismutase (SOD) and paraoxonase-1 (PON1) activities, and decreased plasma IL-6, TNF-α, and MCP-1 levels. Moreover, ISL significantly reduced the atherosclerotic lesions and hepatic steatosis in apoE−/− mice. In the liver, ISL altered the expression of several key genes (such as SRBI, ABCA1, ABCG8, PPARγ, and FASN) involving cholesterol-selective uptake and excretion into bile, triglyceride (TG) biosynthesis, and inflammation. These results suggest that the atheroprotective effects of ISL are due to the improvement of lipid metabolism, antioxidation, and anti-inflammation, which involve PPARγ-dependent signaling.

Highlights

Atherosclerosis is characterized by the development of low-grade arterial inflammatory lesions, and is associated with oxidative stress and dyslipidemia [1,2,3]
The results showed that ox-low-density lipoproteins (LDL) treatment significantly decreased the peroxisome proliferator-activated receptor gamma (PPARγ) protein level in peritoneal macrophages, which was increased in ISL-treated cells (Figure 2a)
In the in vivo study, plasma protein levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and monocyte chemotactic protein-1 (MCP-1) were dramatically decreased in apoE−/− mice fed ISL, and the mRNA levels of IL-6 and TNF-α were decreased in the liver, indicating that ISL achieved its anti-inflammatory activities by inhibiting inflammatory cytokine production, and might possess the ability to attenuate atherosclerosis

Summary

Introduction

Atherosclerosis is characterized by the development of low-grade arterial inflammatory lesions, and is associated with oxidative stress and dyslipidemia [1,2,3]. Lipid accumulation and oxidation induces the release of inflammatory factors within the arterial wall and is responsible for atherosclerotic plaque development [4,5]. Macrophages aggressively take up oxidized lipids, and become foam cells that initiate the formation of atherosclerotic lesions. Macrophage foam cells release proinflammatory cytokines and thereby further exaggerate arterial wall inflammation [7]. Drugs with more comprehensive therapeutic effects on elevated plasma lipids, lipoprotein oxidation, and vascular inflammation will have important clinical value for the treatment and prevention of atherosclerosis [8]

Methods

Results

Discussion

Conclusion