The circadian clock controls hepatic stellate cell activation via a BMAL1/CK1ε/REV-ERBα/transgelin signaling pathway
Abstract
Liver fibrosis is a progressive and life-threatening condition with no effective targeted treatments. Growing evidence indicates a two-way relationship between circadian rhythm and fibrogenesis, although the specific molecular signaling pathways involved are still not well understood. The molecular clock, which governs circadian rhythms, regulates metabolic and cellular functions, and its pharmacological manipulation has shown potential as a therapy for organ fibrosis. Although the liver’s molecular clock appeared resilient to the progression of chronic liver disease in humans from steatosis to fibrosis, detectable changes in the daily amplitude of clock genes were observed in a cohort of people living with obesity. We found a clock-controlled signaling pathway that drives hepatic stellate cell (HSC) activation, a key initiating event in fibrosis progression. Interfering with this pathway, either by disrupting the core regulator CLOCK:BMAL1 or activating the nuclear receptors REV-ERBs, significantly reduced HSC activation. We also identified transgelin as the downstream effector of clock-regulated HSC contractility, a characteristic of HSC activation. Transgelin is regulated indirectly by a BMAL1-CK1ε signaling pathway and directly by REV-ERBα. Our findings identify a hitherto undescribed mechanism that links the molecular clock to HSC activation and cell contractile function, which is relevant to human fibrotic diseases. This pathway provides several entry points for drugs to target and disrupt primary fibrogenic signaling. By connecting clock biology to the cellular processes that cause fibrosis, our work also offers a mechanistic basis for chronotherapeutic strategies against chronic liver disease.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Manuel Johanns
Alexandre Berthier
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Jimmy Vandel
US 41-Unité d‘Appui et de Recherche 2014-Plateformes Lilloises en Biologie et Santé Bilille, CNRS, Inserm, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, Université de Lille
Sandra Courquet
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Marie Lapage
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Julie Dubois-Chevalier
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Manjula Vinod
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Ninon Very
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Francesco Paolo Zummo
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Marie Bobowski-Gérard
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Georgiana Toma
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Céline Gheeraert
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Didier Vertommen
Gaëtan Herinckx
Violeta Raverdy
Inserm, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1190-European Genomic Institute for Diabetes, Université de Lille
François Pattou
Inserm, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1190-European Genomic Institute for Diabetes, Université de Lille
Bart Staels
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Jérôme Eeckhoute
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille
Philippe Lefebvre
Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, UMR1011-European Genomic Institute for Diabetes, Université de Lille