Circadian Clock Gene Bmal1 Regulates Bilirubin Detoxification: A Potential Mechanism of Feedback Control of Hyperbilirubinemia

Aug 15, 2019Theranostics

The Body Clock Gene Bmal1 Controls Bilirubin Breakdown and May Help Manage High Bilirubin Levels

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Abstract

Circadian variations in plasma unconjugated bilirubin (UCB) levels were observed, which were antiphase to the expressions of detoxifying genes Ugt1a1 and Mrp2.

Bmal1, a core clock gene, plays a critical role in regulating bilirubin detoxification and homeostasis.
Ablation of Bmal1 disrupted the circadian rhythms of UCB levels and increased susceptibility to bilirubin-induced liver toxicity in mice.
Bmal1 ablation decreased the expression of Ugt1a1 and Mrp2, which are key enzymes in bilirubin detoxification.
Bmal1 was shown to directly activate Ugt1a1 and Mrp2 through specific binding to their promoter regions.
Bilirubin stimulated Bmal1 expression, indicating a feedback mechanism that contributes to bilirubin detoxification.

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Controlling bilirubin to a low level is necessary in physiology because of its severe neurotoxicity. Therefore, it is of great interest to understand the regulatory mechanisms for bilirubin homeostasis. In this study, we uncover a critical role for circadian clock in regulation of bilirubin detoxification and homeostasis.: The mRNA and protein levels of Bmal1 (a core clock gene), metabolic enzymes and transporters were measured by qPCR and Western blotting, respectively. Luciferase reporter, mobility shift and chromatin immunoprecipitation were used to investigate transcriptional gene regulation. Experimental hyperbilirubinemia was induced by injection of bilirubin or phenylhydrazine. Unconjugated bilirubin (UCB) and conjugated bilirubin were assessed by ELISA.: We first demonstrated diurnal variations in plasma UCB levels and in main bilirubin-detoxifying genesand. Of note, the circadian UCB levels were antiphase to the circadian expressions of Ugt1a1 and Mrp2. Bmal1 ablation abrogated the circadian rhythms of UCB and bilirubin-induced hepatotoxicity in mice. Bmal1 ablation also decreased mRNA and protein expressions of both Ugt1a1 and Mrp2 in mouse livers, and blunted their circadian rhythms. A combination of luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Bmal1 trans-activatedandthrough specific binding to the E-boxes in the promoter region. Further, Bmal1 ablation caused a loss of circadian time-dependency in bilirubin clearance and sensitized mice to chemical induced-hyperbilirubinemia. Moreover, bilirubin stimulated Bmal1 expression through antagonism of Rev-erbα, constituting a feedback mechanism in bilirubin detoxification.: These data supported a dual role for circadian clock in regulation of bilirubin detoxification, generating circadian variations in bilirubin level via direct transactivation of detoxifying genes Ugt1a1 and Mrp2, and defending the body against hyperbilirubinemia via Rev-erbα antagonism. Thereby, our study provided a potential mechanism for management of bilirubin related diseases. Methods Results Conclusion Ugt1a1Mrp2Ugt1a1Mrp2

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Circadian Clock Gene Bmal1 Regulates Bilirubin Detoxification: A Potential Mechanism of Feedback Control of Hyperbilirubinemia

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