Regulatory Biology Laboratory (A.C., T. Lin, T. Le, C.L., S.P.), Salk Institute for Biological Studies, La Jolla, CA.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City (A.C.).
Arterioscler Thromb Vasc Biol. 2024 Sep;44(9):2069-2087. doi: 10.1161/ATVBAHA.124.320998. Epub 2024 Aug 1.
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.
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.
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.
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.
血脂异常会增加心血管疾病的风险，这是全球范围内的主要致死原因。在限时进食（TRF）中，即限制在 12 小时内进食，喂食致肥胖饮食的小鼠体重增加、葡萄糖耐量降低、炎症、血脂异常和高胆固醇血症均会减少。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。
我们对基准临床前模型进行了研究，即缺乏 LDLR 基因敲除或 ApoE 基因敲除的小鼠，给予等热量的致动脉粥样硬化饮食，自由进食或限时进食 9 小时，持续长达 13 周，评估疾病发展、机制以及肝脏基因表达和血浆脂质的整体变化。在回归模型中，一部分 LDLR 基因敲除的小鼠进行自由进食，然后进行限时进食。
TRF 可显著减轻缺乏 LDLR 基因敲除小鼠在实验条件下的体重增加、高胆固醇血症和动脉粥样硬化。在 LDLR 基因敲除小鼠中，禁食期间介导β-氧化的基因在肝脏中的表达增加与 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，加上胆固醇和胆汁酸的粪便丢失，有助于 TRF 的抗动脉粥样硬化作用。最后，TRF 单独或与无胆固醇饮食联合使用可减少 LDLR 基因敲除小鼠的动脉粥样硬化。但是，缺乏 ApoE 的小鼠则不会对 TRF 产生反应，ApoE 是肝脏脂蛋白再摄取的重要蛋白。
在临床前动物模型中，TRF 对 LDLR 基因敲除小鼠的动脉粥样硬化的预防和逆转均有效。结果表明，TRF 单独或与低胆固醇饮食联合使用可能是降低人类心血管疾病风险的生活方式干预措施。
