Coordinated Signaling of Activating Transcription Factor 6α and Inositol Requiring Enzyme 1α Regulates Hepatic Stellate Cell-Mediated Fibrogenesis in Mice.

BACKGROUND/AIMS: 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 IRE1α, ATF6α, and PERK, previous research in HSCs primarily focused on IRE1α. Here, we interrogated the fibrogenic role of ATF6α or PERK in vitro and HSC-specific UPR signaling in vivo.

METHODS/RESULTS: Overexpression of ATF6α, but not the PERK effector ATF4, promoted HSC activation and fibrogenic gene transcription in immortalized HSCs. Furthermore, ATF6α inhibition through Ceapin-A7, or Atf6a deletion, disrupted TGFβ-mediated activation of primary hHSCs or mHSCs respectively. We interrogated the fibrogenic role of ATF6α in vivo through conditional HSC-specific Atf6a deletion. Atf6aHSCΔ/Δ mice displayed reduced fibrosis and HSC activation following bile-duct ligation (BDL) or CCl4 -induced injury. The Atf6aHSCΔ/Δ phenotype differed from HSC-specific Ire1a deletion, as Ire1aHSCΔ/Δ mice showed reduced fibrogenic gene transcription no changes in fibrosis compared to Ire1afl/fl mice following BDL. Interestingly, ATF6α signaling increased in Ire1aΔ/Δ HSCs, while IRE1α signaling was upregulated in Atf6aΔ/Δ HSCs. Finally, we asked whether co-deletion of Arf6a and Ire1a additively limits fibrosis. Unexpectedly, fibrosis worsened in Atf6aHSCΔ/Δ Ire1aHSCΔ /Δ mice following BDL, and Atf6aΔ/Δ Ire1aΔ/Δ mHSCs showed increased fibrogenic gene transcription.

CONCLUSIONS: ATF6α and IRE1α individually promote fibrogenic transcription in HSCs and ATF6α 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.