限时喂养可减少 LDLR KO 小鼠的动脉粥样硬化,但不能减少 ApoE 基因敲除小鼠的动脉粥样硬化。

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-09-01 Epub Date: 2024-08-01 DOI:10.1161/ATVBAHA.124.320998
Amandine Chaix, Terry Lin, Bastian Ramms, Roy G Cutler, Tiffani Le, Catherine Lopez, Phuong Miu, Antonio F M Pinto, Alan Saghatelian, Martin P Playford, Nehal N Mehta, Mark P Mattson, Philip Gordts, Joseph L Witztum, Satchidananda Panda
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引用次数: 0

摘要

背景:血脂异常会增加心血管疾病的风险,而心血管疾病是导致全球死亡的主要原因。在限时喂养(TRF)条件下,食物摄入被限制在一个持续的时间窗口内:我们以临床前模型为基准,让缺乏 LDLR 基因敲除或 ApoE 基因敲除的小鼠自由进食等热量致动脉粥样硬化饮食或 9 小时 TRF 长达 13 周,并评估疾病的发展、机制以及肝脏基因表达和血浆脂质的整体变化。在一个回归模型中,一部分 LDLR 基因敲除的小鼠在自由饮食的基础上再摄入 TRF:结果:在预防和回归实验条件下,TRF能明显减轻LDLR基因敲除小鼠的体重增加、高胆固醇血症和动脉粥样硬化。在 LDLR 基因敲除小鼠中,空腹时肝脏介导 β 氧化的基因表达增加与 VLDL(极低密度脂蛋白)分泌和脂质积累减少有关。此外,固醇分解的增加以及粪便中胆固醇和胆汁酸的流失也有助于 TRF 对动脉粥样硬化的保护作用。最后,单独使用 TRF 或与不含胆固醇的饮食结合使用可减少 LDLR 基因敲除小鼠的动脉粥样硬化。然而,缺乏载脂蛋白E(肝脏脂蛋白再摄取的重要蛋白)的小鼠对TRF没有反应:结论:在临床前动物模型中,TRF 对 LDLR 基因敲除小鼠动脉粥样硬化的预防和消退均有效。结论:在临床前动物模型中,TRF 对低密度脂蛋白胆固醇剔除小鼠的动脉粥样硬化的预防和缓解均有效。
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Time-Restricted Feeding Reduces Atherosclerosis in LDLR KO Mice but Not in ApoE Knockout Mice.

Background: Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease.

Methods: We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF.

Results: TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF.

Conclusions: In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.

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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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