Alternate day fasting aggravates atherosclerosis through the suppression of hepatic ATF3 in Apoe^(-/-)mice  

作　　者：Yajuan Deng Xiaoyu Yang Xueru Ye Youwen Yuan Yanan Zhang Fei Teng Danming You Xuan Zhou Wenhui Liu Kangli Li Shenjian Luo Zhi Yang Ruxin Chen Guojun Shi Jin Li Huijie Zhang 

机构地区：[1]Department of Endocrinology and Metabolism,Nanfang Hospital,Southern Medical University,Guangzhou,Guangdong 510515,China [2]Guangdong Provincial Key Laboratory of Shock and Microcirculation,Nanfang Hospital,Southern Medical University,Guangzhou,Guangdong 510515,China [3]State Key Laboratory of Organ Failure Research,National Clinical Research Center for Kidney Disease,Nanfang Hospital,Southern Medical University,Guangzhou,Guangdong 510515,China [4]Department of Endocrinology,The Second Hospital of Shanxi Medical University,Shanxi Medical University,Taiyuan,Shanxi 030001,China [5]Department of Endocrinology and Metabolism,Guangdong Provincial Key Laboratory of Diabetology,The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510630,China

出　　处：《Life Metabolism》2024年第3期46-59,共14页生命代谢（英文）

基　　金：supported by grants from the National Science Fund for Distinguished Young Scholars(82325011);the Joint Funds of the National Natural Science Foundation of China(U22A20288);the National Key Research and Development Project(2018YFA0800404);the National Natural Science Foundation of China(81970736);the Key-Area Clinical Research Program of Southern Medical University(LC2019ZD010 and 2019CR022).

摘　　要：Atherosclerosis is the major contributor to cardiovascular mortality worldwide.Alternate day fasting(ADF)has gained growing attention due to its metabolic benefits.However,the effects of ADF on atherosclerotic plaque formation remain inconsistent and controversial in atherosclerotic animal models.The present study was designed to investigate the effects of ADF on atherosclerosis in apolipoprotein E-deficient(Apoe^(-/-))mice.Eleven-week-old male Apoe^(-/-)mice fed with Western diet(WD)were randomly grouped into ad libitum(AL)group and ADF group,and ADF aggravated both the early and advanced atherosclerotic lesion formation,which might be due to the disturbed cholesterol profiles caused by ADF intervention.ADF significantly altered cholesterol metabolism pathways and down-regulated integrated stress response(ISR)in the liver.The hepatic expression of activating transcription factor 3(ATF3)was suppressed in mice treated with ADF and hepatocyte-specific overexpression of Aft3 attenuated the effects of ADF on atherosclerotic plaque formation in Apoe^(-/-)mice.Moreover,the expression of ATF3 could be regulated by Krüppel-like factor 6(KLF6)and both the expressions of ATF3 and KLF6 were regulated by hepatic cellular ISR pathway.In conclusion,ADF aggravates atherosclerosis progression in Apoe^(-/-)mice fed on WD.ADF inhibits the hepatic ISR signaling pathway and decreases the expression of KLF6,subsequently inhibiting ATF3 expression.The suppressed ATF3 expression in the liver mediates the deteriorated effects of ADF on atherosclerosis in Apoe^(-/-)mice.The findings suggest the potentially harmful effects when ADF intervention is applied to the population at high risk of atherosclerosis.

关 键 词：alternate day fasting ATHEROSCLEROSIS CHOLESTEROL integrated stress response activating transcription factor 3 

分 类 号：R543.5[医药卫生—心血管疾病]