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

描述（由申请人提供）：昼夜节律紊乱与人类代谢综合征和肥胖相关，导致葡萄糖、胰岛素和脂质的稳态调节改变。胆汁酸是运输和吸收营养物质和代谢物所必需的生理清洁剂，也是调节脂质和葡萄糖能量代谢和体内平衡的细胞信号通路中的核受体底物。胆固醇7?的转录活性-羟化酶（CYP7A1）是胆固醇转化为胆汁酸的限速酶，受到细胞环境成分的严格调控，包括胆汁酸、营养可利用性、胰岛素等因素。最近的研究也表明，CYP7A1在啮齿动物和人类中表现出昼夜节律的表达，这种节律在饮食和喂养时间改变的情况下发生改变，导致胆汁酸稳态和代谢的调节受到干扰。本实验将在睡眠剥夺和高脂肪喂养的CYP7A1人源化小鼠模型中进一步研究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型糖尿病和肥胖的机制。

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.