Abstract
Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.
Highlights
Metabolism is a major defense mechanism of the body against xenobiotic threats
Disruption of circadian rhythms has been linked to various health problems such as sleep disorders, obesity, diabetes, and cancers[1]
We aimed to investigate the role of the core clock component Bmal[1] in circadian regulation of Cyp3a11, and to determine the molecular mechanisms involved
Summary
We unravel a critical role of Bmal[1] for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal[1] deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Bmal[1] connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time. All circadian clocks are composed of a network of genes/proteins that form several feedback circuits[5]. The main circuit consists of BMAL1 (brain and muscle ARNT-like 1, ARNT1) and CLOCK (circadian locomotor output cycles kaput)
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