Sleep deprivation (SD) causes circadian misalignment, and circadian clock disruption is associated with metabolic diseases such as obesity, insulin resistance, and diabetes. However, the underlying mechanism for SD-induced circadian clock disruption as well as metabolic enzyme changes is still lacking. Here, we developed SD sensitizes mice with disrupted circadian rhythms to demonstrate the regulation role and mechanism of SD in UDP-glucuronosyltransferases (UGTs) expression and the metabolism of corresponding substrates. We found that UGT Family 1 Member A9 (UGT1A9) expression was significantly decreased in the liver of SD mice, which led to an elevation exposure and prolonged anesthesia effect of propofol, which was attributed to the decreased metabolism. Meanwhile, SD down-regulated basic helix-loop-helix ARNT like 1 (BMAL1) and its target clock genes period circadian clock (Per), cryptochrome circadian regulator (Cry), and nuclear receptor subfamily 1 group D member 1 (Rev-erb) expression in mice. Furthermore, the positive regulation of UGTIA9 mRNA and protein levels by Bmal1 was confirmed in hepatocyte-specific Bmal1-knockout mice (Bmal1-hkO) and Bmal1-overexpressed AML-12 cells. At last, through a combination of promoter analysis, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay, it was conducted that Bmal1 regulates Ugtla9 expression by directly binding the -864 bp E-box in Ugtla9 promotor or indirectly acting on the Rev-erbα- differentiated embryo chondrocyte 2 (Dec2) axis. In conclusion, our findings suggested that SD can lead to altered drug disposition and effects in vivo, and Bmal1 plays a crucial role in the crosstalk between SD-induced circadian clock disruption and drug metabolism. It initiates a new direction for the understanding of drug efficacy and toxicity changes in SD conditions and provides a scientific basis for improving the rationality of drug use.
