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

睡眠剥夺和高脂饮食对人体CYP7A1昼夜节律的影响

• 批准号: 8495068
• 负责人: Jessica Marie Ferrell
• 金额: $ 5.39万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495068
• 关键词: Adult; Affect; Animals; Bile Acid Biosynthesis Pathway; Bile Acids; Biological Clocks; Blood Glucose; CYP7A1 gene; Cholesterol; Cholesterol 7-alpha-Monooxygenase; Cholesterol Homeostasis; Circadian Rhythms; Coupled; Data; Detergents; Developed Countries; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Energy Metabolism; Ensure; Environment; Enzymes; Exhibits; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Genes; Glucose; Hepatic; Homeostasis; Hour; Human; Hyperglycemia; Hyperlipidemia; Hypertriglyceridemia; Incidence; Insulin; Insulin Resistance; Jet Lag Syndrome; Knockout Mice; Lead; Ligands; Lipids; Liver; Liver diseases; Malnutrition; Metabolic; Metabolic syndrome; Metabolism; Mixed Function Oxygenases; Modeling; Motor Activity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutrient; Obesity; Pathogenesis; Pathway interactions; Pattern; Peripheral; Phenotype; Physiological; Physiological Processes; Play; Population; Prevalence; Regulation; Research; Rodent; Role; Rotation; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Societies; Testing; The Sun; Time; United States; absorption; blood glucose regulation; feeding; glucose metabolism; insight; lipid metabolism; liver metabolism; mouse model; non-alcoholic fatty liver; public health relevance; research study; shift work

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.

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。胆汁酸是营养物质和代谢物的运输和吸收所必需的生理洗涤剂，并且还在调节脂质和葡萄糖能量代谢和稳态的细胞信号传导途径中充当核受体底物。胆固醇7的转录活性？-羟化酶（CYP 7A 1）是胆固醇转化为胆汁酸的限速酶，受细胞环境组分（包括胆汁酸、营养物质利用率、胰岛素和其他因素）的严格调节。最近的研究还表明，CYP 7A 1在啮齿动物和人类中表现出昼夜节律的表达，并且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的调节紊乱。拟议的实验将进一步研究昼夜节律和肝脏代谢在经历睡眠剥夺和高脂肪喂养的CYP 7A 1人源化小鼠模型中的相互作用，以阐明昼夜节律失调导致人类II型糖尿病和肥胖的机制。