SAT-155 Temporal Activation of the Unfolded Protein Response and Concomitant Downregulation of Key Hepatic Transcription Factors in Critical Illness

Abstract

Background: Critically ill patients often develop multiple organ failure accompanied by profound metabolic and endocrine alterations. The pathogenesis is incompletely understood, but the development of cellular stress, including endoplasmic reticulum (ER) stress, might play a pivotal role (1). Indeed, markers of ER stress have been observed in critical illness, both in animal models and human patients, correlating with organ dysfunction (1). ER stress normally activates the unfolded protein response (UPR). The UPR follows a distinct temporal pattern, aimed at restoring ER homeostasis in the short term, but inducing apoptosis whenever ER stress becomes too severe or prolonged. During critical illness, the temporal activation pattern in liver has only been partially studied. In addition, the potential implications for liver function and metabolism are currently unknown. Methods: We quantified the hepatic expression of crucial markers of the 3 UPR branches and of key hepatic transcription factors in a clinically relevant fluid-resuscitated mouse model of sepsis. Mice were sacrificed at 10 hrs, 30 hrs or 3 days after cecal ligation and puncture in comparison with healthy pair-fed mice (n=15 per group per time point). We quantified the same markers in postmortem liver biopsies from patients admitted to the intensive care unit with sepsis (n=64), who died after a median ICU stay of 10 days (IQR 6-20 days), in comparison with matched patients undergoing elective restorative rectal surgery (n=18). Results: In septic mice, the UPR showed a distinct temporal pattern. In the acute phase (10-30 hrs), the PERK, IRE1α and ATF6 branches were all activated (p˂0.01). In the prolonged phase (3 days), the PERK and ATF6 branches were attenuated and only the IRE1α branch remained activated (p˂0.0001). The UPR activation in the acute phase coincided with a significant downregulation of key hepatic transcription factors important for normal liver function and metabolism, including Shp, FXR, Lrh1, PXR, Hnf6 and Foxa2 (p˂0.01). Several transcription factors remained significantly downregulated in the prolonged phase. ALT as liver damage marker correlated directly with several UPR markers and inversely with several transcription factors in the acute phase, but not in the prolonged phase. In postmortem liver biopsies of patients with sepsis, we only observed an upregulation of the IRE1α branch of the UPR, consistent with the pattern in prolonged critically ill mice. Also in patients, this coincided with a repression of several key hepatic transcription factors. Conclusion: The present findings suggest that patients admitted to the intensive care unit with sepsis develop a state of chronic ER stress in the liver, which might hamper normal hepatic function at least in part through the downregulation of key transcription factors.