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| Status |
Public on Feb 28, 2024 |
| Title |
Circadian rhythm-dependent programs control inflammatory responses and drug metabolism in primary human hepatocytes II. |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Various aspects of physiology and cell function present self-sustained ~24h variations termed circadian rhythms, enabling anticipation and adaptation to the 24-h cycle produced by the Earth’s rotation. The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus, and peripheral clocks present in distinct tissues. In particular, peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis. Here, we established and characterized a human hepatocyte in vitro system in which human primary hepatocytes displayed self-sustained oscillations independently of external cues a distinguishing feature of circadian clocks. We then used this experimental system to study the impact of circadian oscillations in human liver pathophysiology. By generating hepatocyte circadian transcriptomes, we demonstrated that the transcriptional state of cultured human hepatocytes is dynamic across 24h. Analyses of gene expression data identified a set of cycling genes, including a subset of well-established ‘core clock genes’ and oscillating genes related to inflammation, drug metabolism, and energy homeostasis. We documented a circadian-dependent induction of the pro-inflammatory cytokines IL-1b, IL-6, TNF-a CXCLl1 and CXCL10 triggered by LPS or IFN-b in human hepatocytes. We also demonstrated circadian fluctuations of a subset of drug metabolism enzymes, which regulate drug pharmacokinetics. Among these enzymes, we identified CYP3A4, as one displaying circadian fluctuations at activity levels and a time-dependent induction with rifampin. Finally, we showed the impact of applying chronopharmacotherapy by designing a treatment protocol to minimize atorvastatin and acetaminophen induced hepatotoxicity. Collectively, our findings document that circadian time can influence the magnitude of the inflammatory response in the liver and the efficacy, toxicity, and/or the therapeutic index of drugs.
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| Overall design |
Two replicates each of primary human hepatocytes cultured with supporting J2-3T3 fibroblasts collected treated with siRNA targeting BmalI (ARNTL) or a non-targeting control for 24 hours and collected at 36, 42,48 or 54 hours
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| Contributor(s) |
Nerurkar N, March S, Whittaker CA, Bhatia S |
| Citation(s) |
38657074 |
| |
| Submission date |
Nov 17, 2022 |
| Last update date |
May 10, 2024 |
| Contact name |
Charles Arthur Whittaker |
| E-mail(s) |
charliew@mit.edu
|
| Organization name |
Koch Institute
|
| Street address |
77 Mass Ave 76-189
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02152 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL25526 |
Illumina NovaSeq 6000 (Homo sapiens; Mus musculus) |
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| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE218244 |
Circadian rhythm-dependent programs control inflammatory responses and drug metabolism in primary human hepatocytes |
|
| Relations |
| BioProject |
PRJNA902797 |
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