| First Author | Stavropoulos A | Year | 2022 |
| Journal | Sci Signal | Volume | 15 |
| Issue | 740 | Pages | eabn4395 |
| PubMed ID | 35763560 | Mgi Jnum | J:347441 |
| Mgi Id | MGI:7512848 | Doi | 10.1126/scisignal.abn4395 |
| Citation | Stavropoulos A, et al. (2022) Coordinated activation of TGF-beta and BMP pathways promotes autophagy and limits liver injury after acetaminophen intoxication. Sci Signal 15(740):eabn4395 |
| abstractText | Ligands of the transforming growth factor-beta (TGF-beta) superfamily, including TGF-betas, 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-betas and activins (TGF-beta/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-beta/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-beta 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-beta1 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-beta superfamily signaling system, implicate the coordinated activation of TGF-beta/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. |
