Intermittent Fasting Inhibits High-Fat Diet-Induced Atherosclerosis by Ameliorating Hypercholesterolemia and Reducing Monocyte Chemoattraction.

Yuanli Chen,Xiaoyu He,Jiamin Su,Yajun Duan,Baotong Zhang,Hongmei Xu,Xiaoxiao Yang,Jihong Han,Mengmeng Zhu,Yali Yan,Jialing Ma,Qian Zhao

doi:10.3389/fphar.2021.719750

Abstract

Atherosclerosis is a major pathology for cardiovascular diseases (CVDs). Clinically, the intermittent fasting (IF) has been observed to reduce the risk of CVDs. However, the effect of IF on the development of atherosclerosis has not been fully elucidated. Herein, we determined the protection of IF against high-fat diet–induced atherosclerosis in pro-atherogenic low-density lipoprotein receptor deficient (LDLR-/-) mice and the potentially involved mechanisms. The LDLR-/- mice were scheduled intermittent fasting cycles of 3-day HFD feeding ad libitum and 1 day fasting, while the mice in the control group were continuously fed HFD. The treatment was lasted for 7 weeks (∼12 cycles) or 14 weeks (∼24 cycles). Associated with the reduced total HFD intake, IF substantially reduced lesions in the en face aorta and aortic root sinus. It also increased plaque stability by increasing the smooth muscle cell (SMC)/collagen content and fibrotic cap thickness while reducing macrophage accumulation and necrotic core areas. Mechanistically, IF reduced serum total and LDL cholesterol levels by inhibiting cholesterol synthesis in the liver. Meanwhile, HFD-induced hepatic lipid accumulation was attenuated by IF. Interestingly, circulating Ly6Chigh monocytes but not T cells and serum c-c motif chemokine ligand 2 levels were significantly reduced by IF. Functionally, adhesion of monocytes to the aortic endothelium was decreased by IF via inhibiting VCAM-1 and ICAM-1 expression. Taken together, our study indicates that IF reduces atherosclerosis in LDLR-/- mice by reducing monocyte chemoattraction/adhesion and ameliorating hypercholesterolemia and suggests its potential application for atherosclerosis treatment.

Highlights

Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality worldwide
Expression of hydroxy-3-methylglutaryl-CoA reductase (HMGCR), HMGC synthase (HMGCS), sterol-responsive element binding protein 2 (SREBP2), ATP-binding cassette transporter A1 (ABCA1), ABCG1/5/8, scavenger receptor class B type I (SR-BI), cholesterol 7-α hydroxylase (CYP7A1), apolipoprotein B, and apoE mRNA in the liver and expression of COL1A1, COL3A1, matrix metallopeptidase 2 (MMP2), and MMP9 in the aorta were normalized by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in the corresponding samples
We previously reported that ∼40% calorie restriction inhibited atherosclerosis via attenuating body weight gain, improving lipid profiles, and inhibiting the expression of inflammatory molecules in lesions (Yang et al, FIGURE 5 | Intermittent fasting reduces high-fat diet (HFD)-induced lipid accumulation in the liver by reducing cholesterol synthesis. (A) Liver photos and hematoxylin and eosin (HE) staining of liver paraffin sections

Summary

INTRODUCTION

Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality worldwide. Three kinds of IF methods, alternate-day fasting, modified fasting regimens, and time-restricted feeding (TRF), have been applied to humans and rodent models to reduce body weight (Patterson and Sears, 2017). Their effect on glucose-regulatory markers, serum lipid profiles, and inflammation are controversial. The modified fasting regimens have been demonstrated to reduce body weight, improve lipid profiles, and reduce inflammation, while increasing self-confidence and positive mood in many studies (Johnson et al, 2007; Varady et al, 2013; Hoddy et al, 2016).

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