Coordinated activation of TGF-β and BMP pathways promotes autophagy and limits liver injury after acetaminophen intoxication.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Association for the Advancement of Science
    • Subject Terms:
      Acetaminophen*/poisoning ; Bone Morphogenetic Proteins*/genetics ; Bone Morphogenetic Proteins*/metabolism ; Chemical and Drug Induced Liver Injury*/etiology ; Chemical and Drug Induced Liver Injury*/genetics ; Chemical and Drug Induced Liver Injury*/metabolism ; Transforming Growth Factor beta*/genetics ; Transforming Growth Factor beta*/metabolism; Activins/metabolism ; Animals ; Autophagy ; Liver/drug effects ; Liver/metabolism ; Mice ; Signal Transduction/drug effects
    • Abstract:
      Ligands of the transforming growth factor-β (TGF-β) superfamily, including TGF-βs, activins, and bone morphogenetic proteins (BMPs), have been implicated in hepatic development, homeostasis, and pathophysiology. We explored the mechanisms by which hepatocytes decode and integrate injury-induced signaling from TGF-βs and activins (TGF-β/Activin) and BMPs. We mapped the spatiotemporal patterns of pathway activation during liver injury induced by acetaminophen (APAP) in dual reporter mice carrying a fluorescent reporter of TGF-β/Activin signaling and a fluorescent reporter of BMP signaling. APAP intoxication induced the expression of both reporters in a zone of cells near areas of tissue damage, which showed an increase in autophagy and demarcated the borders between healthy and injured tissues. Inhibition of TGF-β superfamily signaling by overexpressing the inhibitor Smad7 exacerbated acute liver histopathology but eventually accelerated tissue recovery. Transcriptomic analysis identified autophagy as a process stimulated by TGF-β1 and BMP4 in hepatocytes, with Trp53inp2 , which encodes a rate-limiting factor for autophagy initiation, as the most highly induced autophagy-related gene. Collectively, these findings illustrate the functional interconnectivity of the TGF-β superfamily signaling system, implicate the coordinated activation of TGF-β/Activin and BMP pathways in balancing tissue reparatory and regenerative processes upon APAP-induced hepatotoxicity, and highlight opportunities and potential risks associated with targeting this signaling system for treating hepatic diseases.
    • Accession Number:
      0 (Bone Morphogenetic Proteins)
      0 (Transforming Growth Factor beta)
      104625-48-1 (Activins)
      362O9ITL9D (Acetaminophen)
    • Publication Date:
      Date Created: 20220628 Date Completed: 20220630 Latest Revision: 20220810
    • Publication Date:
      20240105
    • Accession Number:
      10.1126/scisignal.abn4395
    • Accession Number:
      35763560