| First Author | Xue F | Year | 2021 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 320 |
| Issue | 5 | Pages | G864-G879 |
| PubMed ID | 33728997 | Mgi Jnum | J:308769 |
| Mgi Id | MGI:6741476 | Doi | 10.1152/ajpgi.00453.2020 |
| Citation | Xue F, et al. (2021) Coordinated signaling of activating transcription factor 6alpha and inositol-requiring enzyme 1alpha regulates hepatic stellate cell-mediated fibrogenesis in mice. Am J Physiol Gastrointest Liver Physiol 320(5):G864-G879 |
| abstractText | Liver injury and the unfolded protein response (UPR) are tightly linked, but their relationship differs with cell type and injurious stimuli. UPR initiation promotes hepatic stellate cell (HSC) activation and fibrogenesis, but the underlying mechanisms are unclear. Despite the complexity and overlap downstream of UPR transducers inositol-requiring protein 1alpha (IRE1alpha), activating transcription factor 6alpha (ATF6alpha), and protein kinase RNA-like ER kinase (PERK), previous research in HSCs primarily focused on IRE1alpha. Here, we investigated the fibrogenic role of ATF6alpha or PERK in vitro and HSC-specific UPR signaling in vivo. Overexpression of ATF6alpha, but not the PERK effector activating transcription factor 4 (ATF4), promoted HSC activation and fibrogenic gene transcription in immortalized HSCs. Furthermore, ATF6alpha inhibition through Ceapin-A7, or Atf6a deletion, disrupted transforming growth factor beta (TGFbeta)-mediated activation of primary human hepatic stellate cells (hHSCs) or murine hepatic stellate cells (mHSCs), respectively. We investigated the fibrogenic role of ATF6alpha in vivo through conditional HSC-specific Atf6a deletion. Atf6a(HSCDelta/Delta) mice displayed reduced fibrosis and HSC activation following bile duct ligation (BDL) or carbon tetrachloride (CCl4)-induced injury. The Atf6a(HSCDelta/Delta) phenotype differed from HSC-specific Ire1a deletion, as Ire1a(HSCDelta/Delta) mice showed reduced fibrogenic gene transcription but no changes in fibrosis compared with Ire1a(fl/fl) mice following BDL. Interestingly, ATF6alpha signaling increased in Ire1a(Delta/Delta) HSCs, whereas IRE1alpha signaling was upregulated in Atf6a(Delta/Delta) HSCs. Finally, we asked whether co-deletion of Atf6a and Ire1a additively limits fibrosis. Unexpectedly, fibrosis worsened in Atf6a(HSCDelta/Delta)Ire1a(HSCDelta/Delta) mice following BDL, and Atf6a(Delta/Delta)Ire1a(Delta/Delta) mHSCs showed increased fibrogenic gene transcription. ATF6alpha and IRE1alpha individually promote fibrogenic transcription in HSCs, and ATF6alpha drives fibrogenesis in vivo. Unexpectedly, disruption of both pathways sensitizes the liver to fibrogenesis, suggesting that fine-tuned UPR signaling is critical for regulating HSC activation and fibrogenesis.NEW & NOTEWORTHY ATF6alpha is a critical driver of hepatic stellate cell (HSC) activation in vitro. HSC-specific deletion of Atf6a limits fibrogenesis in vivo despite increased IRE1alpha signaling. Conditional deletion of Ire1alpha from HSCs limits fibrogenic gene transcription without impacting overall fibrosis. This could be due in part to observed upregulation of the ATF6alpha pathway. Dual loss of Atf6a and Ire1a from HSCs worsens fibrosis in vivo through enhanced HSC activation. |
