Effects of sleep deprivation and high fat diet on human CYP7A1 circadian rhythm

描述(申请人提供)：昼夜节律紊乱与人类的代谢综合征和肥胖有关，导致葡萄糖、胰岛素和血脂的动态平衡调节改变。胆汁酸是营养物质和代谢物运输和吸收所必需的生理洗涤剂，也是细胞信号通路中的核受体底物，调节脂肪和葡萄糖的能量代谢和动态平衡。胆固醇7？羟基酶(CyP7A1)是胆固醇转化为胆汁酸的限速酶，其转录活性受到细胞环境成分的严格调控，包括胆汁酸、营养物质的可获得性、胰岛素和其他因素。最近的研究还表明，CYP7A1在啮齿动物和人类中表现出一种昼夜节律，这种节律在改变饮食和进食时间的条件下发生改变，导致胆汁酸稳态和代谢调节的紊乱。拟议的实验将进一步研究在接受睡眠剥夺和高脂肪喂养的CYP7A1人源化小鼠模型中昼夜节律和肝脏代谢的相互作用，以阐明昼夜节律失调导致人类II型糖尿病和肥胖症的机制。 与公共健康相关：胆汁酸是通过人体细胞色素P7A1基因的昼夜节律调节葡萄糖和脂肪代谢来维持能量平衡的关键。糖尿病、肥胖和代谢综合征与由于时差、倒班工作和睡眠不足造成的昼夜节律紊乱有关，而饮食结构的改变会影响外周节律基因的表达。拟议的研究旨在了解去调节的昼夜节律肝脏代谢在糖尿病和肥胖症进展中的作用。

DESCRIPTION (provided by applicant): Circadian rhythm disturbances are associated with metabolic syndrome and obesity in humans, leading to altered homeostatic regulation of glucose, insulin, and lipids. Bile acids are physiological detergents essential for the transport and absorption of nutrients and metabolites, and also act as nuclear receptor substrates in the cell signaling pathways that modulate lipid and glucose energy metabolism and homeostasis. Transcriptional activity of cholesterol 7?-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids, is strictly regulated by components of the cellular environment, including bile acids, nutrient availability, insulin, and other factors. Recent studie also indicate that CYP7A1 displays a diurnal rhythm of expression in rodents and humans, and this rhythm is shifted under conditions of altered diet and time of feeding, leading to disturbed regulation of bile acid homeostasis and metabolism. The proposed experiments will further examine the interactions of circadian rhythms and hepatic metabolism in a CYP7A1 humanized mouse model undergoing sleep deprivation and high-fat feeding to elucidate the mechanisms by which circadian misregulation contributes to Type II diabetes and obesity in humans. PUBLIC HEALTH RELEVANCE: Bile acids are critical for maintaining energy homeostasis through glucose and lipid metabolism via circadian regulation of the human CYP7A1 gene. Diabetes, obesity, and metabolic syndrome are associated with perturbations in circadian rhythms due to jet lag, shift work, and sleep deprivation, while altered diet composition can affect peripheral rhythmic gene expression. The proposed studies aim to understand the contribution of deregulated circadian liver metabolism in the progression of diabetes and obesity.