Increasing evidence indicates that the intra-uterine environment has consequences for later life. However, the mechanisms of this fetal programming remain unclear. We aimed to investigate the impact of diet-induced maternal hypercholesterolemia on the predisposition of offspring to nonalcoholic fatty liver diseases (NAFLD) and metabolic diseases and its underlying mechanisms. Female apolipoprotein (Apo) E-deficient mice were fed a control diet (CD) or high fat/high cholesterol Western-type diet (WD) before and throughout pregnancy and lactation, and their offspring were weaned onto a CD postnatally. Strikingly, male offspring of WD-fed dams developed glucose intolerance and decreased peripheral insulin sensitivity and exhibited hepatic steatosis. Hepatic steatosis could be attributed, at least in part, to increased hepatic lipogenesis in E18.5 embryos and decreased serum VLDL levels in adulthood. In addition, males born to WD-fed dams had lower serum ApoB levels and hepatic ApoB gene expression compared with males born to CD-fed dams. DNA methylation analysis revealed increased methylation of CpG dinucleotides on the promoter region of the ApoB genes in the livers of male offspring of WD-fed dams. Our findings suggest that maternal WD intake can exacerbate the development of NAFLD in male offspring potentially by affecting ApoB gene expression through epigenetic alterations.

越来越多的证据表明子宫内环境对以后的生活有影响。但是，这种胎儿编程的机制仍不清楚。我们旨在调查饮食引起的母体高胆固醇血症对后代易患非酒精性脂肪肝疾病（NAFLD）和代谢性疾病及其基础机制的影响。雌性载脂蛋白（Apo）E缺陷型小鼠在妊娠和哺乳前后以及整个哺乳期都喂以对照饮食（CD）或高脂肪/高胆固醇西式饮食（WD），其后代在出生后断奶到CD上。令人吃惊的是，由WD喂养的水坝的雄性后代出现葡萄糖耐量下降，外周胰岛素敏感性降低，并表现出肝脂肪变性。肝脂肪变性可以至少部分归因于E18肝脂肪生成的增加。5个胚胎，成年后血清VLDL水平降低。此外，由WD喂养的大坝出生的男性的血清ApoB水平和肝脏水平较低与CD喂养的大坝出生的雄性相比，ApoB基因的表达。DNA甲基化分析显示，WD喂养的大坝雄性后代肝脏中，ApoB基因启动子区域的CpG二核苷酸甲基化增加。我们的发现表明，母体WD摄入可能通过表观遗传学改变影响ApoB基因表达，从而加剧雄性后代NAFLD的发展。