2024-04-24 マサチューセッツ工科大学(MIT)
<関連情報>
- https://news.mit.edu/2024/circadian-rhythms-can-influence-drugs-effectiveness-0424
- https://www.science.org/doi/10.1126/sciadv.adm9281
ヒト肝細胞における自律的な概日リズムは、肝薬物代謝と炎症反応を制御する Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses
SANDRA MARCH, NIKETA NERURKAR, ANISHA JAIN, LINDA ANDRUS, […], AND SANGEETA N. BHATIA
Science Advances Published:24 Apr 2024
DOI:https://doi.org/10.1126/sciadv.adm9281
Abstract
Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-β, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver.
