Ferulic Acid Ameliorates Atherosclerotic Injury by Modulating Gut Microbiota and Lipid Metabolism.

Yuyan Gu,Yaxin Zhang,Lihua Zhang,Mei Li,Yihao Chen,Jing Jiang,Junqi Chen,Yuhua Jia,Zhiyong Huang,Fenghua Zhou

doi:10.3389/fphar.2021.621339

Abstract

Atherosclerosis is a leading cause of death worldwide. Recent studies have emphasized the significance of gut microbiota and lipid metabolism in the development of atherosclerosis. Herein, the effects and molecular mechanisms involving ferulic acid (FA) was examined in atherosclerosis using the ApoE-knockout (ApoE-∕-, c57BL/6 background) mouse model. Eighteen male ApoE−/− mice were fed a high-fat diet (HFD) for 12 weeks and then randomly divided into three groups: the model group, the FA (40 mg/kg/day) group and simvastatin (5 mg/kg/day) group. As results, FA could significantly alleviate atherosclerosis and regulate lipid levels in mice. Liver injury and hepatocyte steatosis induced by HFD were also mitigated by FA. FA improved lipid metabolism involving up-regulation of AMPKα phosphorylation and down-regulation of SREBP1 and ACC1 expression. Furthermore, FA induced marked structural changes in the gut microbiota and fecal metabolites and specifically reduced the relative abundance of Fimicutes, Erysipelotrichaceae and Ileibacterium, which were positively correlated with serum lipid levels in atherosclerosis mice. In conclusion, we demonstrate that FA could significantly ameliorate atherosclerotic injury, which may be partly by modulating gut microbiota and lipid metabolism via the AMPKα/SREBP1/ACC1 pathway.

Highlights

Cardiovascular and cerebrovascular diseases, which mainly develop from atherosclerosis, have become the leading cause of death worldwide, especially in developed countries (Liu et al, 2019)
We found that the Aherogenic index (AI) was significantly higher in the model group than that in the control group, while ferulic acid (FA) could significantly reduce the AI (2.17-fold; p < 0.05; Figure 1E)
Since high-fat diet (HFD) always leads to excess cholesterol accumulation in the liver (Feltenberger et al, 2013), the target organ for lipid metabolism, we evaluated the effects of FA on fatty damage in the liver

Summary

Introduction

Cardiovascular and cerebrovascular diseases, which mainly develop from atherosclerosis, have become the leading cause of death worldwide, especially in developed countries (Liu et al, 2019). The atherosclerotic plaque, derived from passive lipid accumulation within the artery wall, is the most significant pathological change of atherosclerosis visible under the microscope (Luo et al, 2015). AMP-activated protein kinase (AMPK), a key regulator of lipid and energy metabolism, can improve lipid metabolism, including lipogenesis, lipolysis, lipid transport, and lipid oxidation (Ma et al, 2017; Park et al, 2017). AMPK reduces lipogenesis by activating sterol regulatory element binding protein 1 (SREBP1) and acetyl-CoA carboxylase (ACC) (Jung et al, 2012; Park et al, 2017), and regulates lipid transport by mediating reverse cholesterol transport (Ma et al, 2017). AMPK modulates lipid oxidation through the AMPK/proliferator-activated receptor-γ coactivator 1α/ peroxisome proliferator-activated receptor α (PPARα) pathway (Araújo et al, 2020)

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