■血脂异常会增加心血管疾病的风险,世界范围内死亡的主要原因。在限时喂食(TRF)下,其中食物摄入被限制在<12小时的一致窗口内,体重增加,葡萄糖不耐受,炎症,血脂异常,和高胆固醇血症在喂养生性饮食的小鼠中都减少了。LDLR(低密度脂蛋白受体)突变是家族性高胆固醇血症和早发性心血管疾病的主要原因。
■我们采用了基准临床前模型,缺乏LDLR敲除或ApoE敲除的小鼠随意喂养等热量致动脉粥样硬化饮食或9小时TRF长达13周,并评估疾病发展,机制,以及肝脏基因表达和血脂的整体变化。在回归模型中,一组LDLR敲除小鼠被随意喂食,然后接受TRF.
■TRF可以显着减轻体重增加,高胆固醇血症,在预防和消退的实验条件下,缺乏LDLR敲除小鼠的动脉粥样硬化。在LDLR敲除小鼠中,禁食期间介导β-氧化的基因的肝脏表达增加与VLDL(极低密度脂蛋白)分泌和脂质积累减少有关。此外,固醇分解代谢增加,胆固醇和胆汁酸的粪便流失有助于TRF的动脉粥样硬化保护作用。最后,TRF单独或与无胆固醇饮食组合可减少LDLR敲除小鼠的动脉粥样硬化。然而,缺乏ApoE的老鼠,它是肝脂蛋白再摄取的重要蛋白质,对TRF无反应。
■在临床前动物模型中,TRF对LDLR敲除小鼠动脉粥样硬化的预防和消退均有效。结果表明,TRF单独或与低胆固醇饮食相结合可以成为降低人类心血管疾病风险的生活方式干预。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.