ATF6 Alleviates Endothelial Inflammation Following Extended Hepatectomy Through Inhibition of TRIM10/NF-κB Signaling

Area of Science:

• Hepatology
• Immunology
• Molecular Biology

Background:

• Postoperative hepatic failure involves inflammation in liver sinusoidal endothelial cells (LSECs).
• The unfolded protein response (UPR) in LSECs is key to resolving inflammation and restoring liver homeostasis after surgery.

Purpose of the Study:

• To investigate the role of activating transcription factor 6 (ATF6) in LSEC inflammation and liver injury following extended hepatectomy.
• To elucidate the molecular mechanisms by which ATF6 regulates endothelial inflammation.

Main Methods:

• Utilized an 80% hepatectomy model in mice and analyzed gene expression in human patients.
• Induced UPR and inflammation in human umbilical vein endothelial cells (HUVECs) using tunicamycin or lipopolysaccharides.
• Investigated ATF6 function through gene knockout, knockdown, and pharmacological manipulation (agonists/antagonists).

Main Results:

• ATF6 was upregulated and activated in LSECs after extended hepatectomy in both mice and humans.
• ATF6 deficiency exacerbated liver injury and inflammatory responses.
• Inhibition of ATF6 in HUVECs led to severe inflammation via the NF-κB pathway, while ATF6 activation ameliorated it.
• ATF6 negatively regulated TRIM10 expression, thereby suppressing NF-κB signaling and endothelial inflammation.

Conclusions:

• ATF6 acts as a crucial suppressor of endothelial inflammation following extended hepatectomy.
• The ATF6-TRIM10/NF-κB signaling pathway is a key mechanism underlying ATF6's protective effects.
• ATF6 presents a potential therapeutic target for preventing or treating postoperative hepatic failure.