Sleep Disturbance Induces Increased Cholesterol Level by NR1D1 Mediated CYP7A1 Inhibition.
Sleep Disturbance Induces Increased Cholesterol Level by NR1D1 Mediated CYP7A1 Inhibition.
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睡眠障碍通过 NR1D1 介导的 CYP7A1 抑制导致胆固醇水平升高
DOI：
10.3389/fgene.2020.610496
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发表时间：
2020
影响因子：
3.7
通讯作者：
Song L
中科院分区：
文献类型：
--
作者：
Xing C;Huang X;Zhang Y;Zhang C;Wang W;Wu L;Ding M;Zhang M;Song L
睡眠紊乱与代谢疾病的风险增加密切相关。然而，与睡眠和脂质异常相关的生物钟基因的潜在机制尚未完全阐明。本研究旨在探讨生物钟在睡眠剥夺（SD）早期调节胆固醇代谢受损中的重要作用。使用SD仪器进行睡眠干扰。我们的研究结果表明，SD增加了血清胆固醇水平。SD后血清瘦素和抵抗素浓度明显降低，但其他代谢激素（脂联素、胰高血糖素、胰岛素、甲状腺素、去甲肾上腺素、肾上腺素）浓度在SD前后没有变化。SD后观察到心血管疾病的预警信号[高密度脂蛋白(HDL)-胆固醇降低，皮质酮和8-羟基鸟苷水平升高]和肝脏胆汁淤积（总胆汁酸和胆红素水平升高）。SD后肝脏中也观察到胆固醇积累。肝脏中合成胆固醇的关键酶HMGCR的表达水平保持不变。然而，肝脏CYP7A1（负责将胆固醇转化为胆汁酸的酶）的表达水平在SD后显著降低。此外，昼夜节律振荡器和CYP7A1的转录调节因子NR1D1的表达在SD后显著降低。此外，NR1D1缺乏可降低肝脏CYP7A1水平，SD可加剧NR1D1−/−小鼠肝脏中CYP7A1表达的降低。此外，NR1D1缺乏可进一步升高SD患者的血清胆固醇水平。这些结果表明，睡眠障碍可通过NR1D1介导的CYP7A1抑制诱导血清胆固醇水平升高和肝脏胆固醇积累。
Disturbed sleep is closely associated with an increased risk of metabolic diseases. However, the underlying mechanisms of circadian clock genes linking sleep and lipid profile abnormalities have not been fully elucidated. This study aimed to explore the important role of the circadian clock in regulating impaired cholesterol metabolism at an early stage of sleep deprivation (SD). Sleep disturbance was conducted using an SD instrument. Our results showed that SD increased the serum cholesterol levels. Concentrations of serum leptin and resistin were much lower after SD, but other metabolic hormone concentrations (adiponectin, glucagon, insulin, thyroxine, norepinephrine, and epinephrine) were unchanged before and after SD. Warning signs of cardiovascular diseases [decreased high density lipoprotein (HDL)-cholesterol and increased corticosterone and 8-hydroxyguanosine levels] and hepatic cholestasis (elevated total bile acids and bilirubin levels) were observed after SD. Cholesterol accumulation was also observed in the liver after SD. The expression levels of HMGCR, the critical enzyme for cholesterol synthesis, remained unchanged in the liver. However, the expression levels of liver CYP7A1, the enzyme responsible for the conversion of cholesterol into bile acids, significantly reduced after SD. Furthermore, expression of NR1D1, a circadian oscillator and transcriptional regulator of CYP7A1, strikingly decreased after SD. Moreover, NR1D1 deficiency decreased liver CYP7A1 levels, and SD could exacerbate the reduction of CYP7A1 expression in NR1D1−/− mouse livers. Additionally, NR1D1 deficiency could further increase serum cholesterol levels under SD. These results suggest that sleep disturbance can induce increased serum cholesterol levels and liver cholesterol accumulation by NR1D1 mediated CYP7A1 inhibition.