Soeda Junpei, Cordero Paul, Li Jiawei, Mouralidarane Angelina, Asilmaz Esra, Ray Shuvra, Nguyen Vi, Carter Rebeca, Novelli Marco, Vinciguerra Manlio, Poston Lucilla, Taylor Paul D, Oben Jude A
a Institute for Liver and Digestive Health, University College London , London , UK.
b Department of Pathology , University College London , London , UK.
Int J Food Sci Nutr. 2017 Jun;68(4):455-466. doi: 10.1080/09637486.2016.1261086. Epub 2016 Nov 29.
We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.
我们研究了健康肝脏以及成年或围产期程序化饮食诱导的非酒精性脂肪性肝病（NAFLD）中肝脏内质网应激的调节情况。在交配前、孕期和哺乳期，给雌性小鼠喂食致肥胖饮食或对照饮食。断奶后，将每个母鼠组的后代分为致肥胖饮食组或对照饮食组。在六个月时，在24小时内每隔4小时处死一批后代。喂食致肥胖饮食的后代出现了NAFLD表型，母代和子代的致肥胖饮食组合加剧了这种表型。未折叠蛋白反应（UPR）信号通路（IREα、PERK、ATF6）及其下游调节因子表现出不同的基础节律性，在暴露于致肥胖饮食和母代程序化的后代中这种节律性发生了改变。双重致肥胖打击增加了通过TUNEL染色、活化的半胱天冬酶-3以及磷酸化JNK和GRP78启动子甲基化水平所检测到的肝脏细胞凋亡。本研究表明肝脏UPR有节律地被激活。母代肥胖（MO）与子代致肥胖饮食的组合引发了UPR节律性、DNA甲基化和细胞凋亡的改变。
