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Nuclear receptor co-repressor RIP140 regulates diurnal expression of cytochrome P450 2b10 in mouse liver

Mengjing Zhao1, Huan Zhao1, Luomin Lin1

  • 1Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|April 3, 2020
PubMed

Insights

Nuclear receptor co-repressor RIP140 regulates the circadian expression of the drug-metabolizing enzyme Cyp2b10 in mice. RIP140

Area of Science:

  • Pharmacology
  • Chronobiology
  • Molecular Biology

Background:

  • Circadian rhythms influence drug metabolism and pharmacokinetics.
  • CYP2B6 (Cyp2b10 in mice) is a key drug-metabolizing enzyme with significant clinical relevance.
  • Understanding the regulation of drug-metabolizing enzymes is crucial for optimizing drug therapy.

Purpose of the Study:

  • To investigate the role of nuclear receptor co-repressor RIP140 in the circadian regulation of Cyp2b10 expression in mice.
  • To elucidate the molecular mechanisms underlying RIP140's regulation of Cyp2b10.
  • To identify potential clock components involved in the rhythmic expression of RIP140.

Main Methods:

  • Analysis of diurnal rhythmicity of RIP140 mRNA and protein in mouse liver.
  • Investigating the effect of RIP140 ablation and overexpression on Cyp2b10 expression.
  • Reporter assays to assess RIP140's effect on Cyp2b10 promoter activity.
  • Chromatin immunoprecipitation assays to determine RIP140 recruitment to the Cyp2b10 promoter.
  • Identification of cis-elements and clock components regulating RIP140 expression.

Main Results:

  • Hepatic RIP140 exhibits diurnal rhythmicity, peaking at ZT10.
  • RIP140 ablation up-regulates Cyp2b10 expression and abolishes its rhythm.
  • RIP140 overexpression inhibits Cyp2b10 promoter activity and reduces its expression.
  • RIP140 suppresses Car- and Pxr-mediated transactivation of Cyp2b10.
  • RIP140 recruitment to the Cyp2b10 promoter is circadian time-dependent.
  • Clock components like Dbp, E4bp4, Rev-erbα/β, and Rorα regulate RIP140 expression.

Conclusions:

  • RIP140 acts as a negative regulator of diurnal Cyp2b10 expression in mouse liver.
  • RIP140 mediates its repressive effect by inhibiting Car- and Pxr-dependent transactivation of Cyp2b10.
  • The circadian expression of RIP140, driven by clock components, contributes to the diurnal rhythmicity of drug-metabolizing enzymes.
  • This study reveals a novel co-regulator-driven mechanism for circadian control of drug metabolism.
Keywords:
CYP2B6Cyp2b10RIP140circadian rhythmco-regulator

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