Department of Endocrinology, Peking University First Hospital, Beijing, China.
Laboratory Animal Facility, Peking University First Hospital, Beijing, China.
J Nutr Biochem. 2023 Dec;122:109449. doi: 10.1016/j.jnutbio.2023.109449. Epub 2023 Sep 24.
Maternal high-calorie diet feeding can dramatically increase the susceptibility of metabolic diseases in offspring. However, whether maternal high-calorie diet feeding can program hepatic cholesterol metabolism in the early life of offspring is less understood, and the epigenetic mechanisms underlying this intergenerational effect, especially during the early life of offspring, are unknown. Female C57BL/6J mice were randomly assigned to a high-calorie diet or control diet before and during gestation, and lactation. Lipid metabolism was evaluated in male offspring at weaning. Gene expressions and quantitative methylation levels of key genes associated with hepatic cholesterol metabolism were further evaluated in offspring at weaning age. We found that maternal high-calorie diet feeding resulted in higher body weight, hypercholesterolemia, elevated total cholesterol in liver homogenates, and fat deposits in the liver in offspring at weaning. For key genes that regulate cholesterol metabolism in liver, we showed lower Hmgcr and Ldlr, and higher Abca1 mRNA and protein expressions in offspring from dams fed with high-calorie diet at weaning age. We further found that maternal high-calorie diet feeding significantly decreased Abca1 methylation level in offspring, with lower methylation levels of both CpG 11 and CpG 22 sites. Interestingly, we found that Abca1 methylation level was negatively associated with hepatic Abca1 mRNA expression in offspring from dams fed with high-calorie diet and controls. However, the expressions of key genes associated with hepatic cholesterol metabolism were not significant between fetuses of dams fed with high-calorie diet and control diet. In conclusion, our results indicate that maternal high-calorie diet feeding results in aberrant lipid metabolism, including hypercholesterolemia and fat deposits in the liver of offspring as early as weaning age. Furthermore, maternal high-calorie feeding can program hepatic cholesterol metabolism and Abca1 methylation in the early life of offspring.
母体高卡路里饮食喂养会显著增加后代代谢疾病的易感性。然而，母体高卡路里饮食喂养是否能在后代的生命早期编程肝脏胆固醇代谢，以及这种代际效应的表观遗传机制，特别是在后代的生命早期，还知之甚少。雌性 C57BL/6J 小鼠在妊娠和哺乳期前和期间被随机分配到高卡路里饮食或对照饮食组。在断奶时评估雄性后代的脂质代谢。在断奶时，进一步评估与肝脏胆固醇代谢相关的关键基因的基因表达和定量甲基化水平。我们发现，母体高卡路里饮食喂养导致后代在断奶时体重增加、高胆固醇血症、肝脏匀浆中总胆固醇升高和肝脏脂肪沉积。对于调节肝脏胆固醇代谢的关键基因，我们发现来自高卡路里饮食喂养的母鼠的后代中 Hmgcr 和 Ldlr 降低，而 Abca1mRNA 和蛋白表达升高。我们进一步发现，母体高卡路里饮食喂养显著降低了后代的 Abca1 甲基化水平，CpG11 和 CpG22 位点的甲基化水平均降低。有趣的是，我们发现来自高卡路里饮食喂养的母鼠的后代中，Abca1 甲基化水平与肝 Abca1mRNA 表达呈负相关，而高卡路里饮食喂养和对照组母鼠的胎儿中关键基因的表达没有显著差异。总之，我们的结果表明，母体高卡路里饮食喂养导致后代脂质代谢异常，包括断奶时的高胆固醇血症和肝脏脂肪沉积。此外，母体高卡路里喂养可以在后代的生命早期编程肝脏胆固醇代谢和 Abca1 甲基化。
