Hepatic Xbp1 Gene Deletion Promotes Endoplasmic Reticulum Stress-induced Liver Injury and Apoptosis.
Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), a highly conserved signaling cascade that functions to alleviate stress and promote cell survival. If, however, the cell is unable to adapt and restore homeostasis, then the UPR activates pathways that promote apoptotic cell death. The molecular mechanisms governing the critical transition from adaptation and survival to initiation of apoptosis remain poorly understood. We aim to determine the role of hepatic Xbp1, a key mediator of the UPR, in controlling the adaptive response to ER stress in the liver. Liver-specific Xbp1 knockout mice (Xbp1(LKO)) and Xbp1(fl/fl) control mice were subjected to varying levels and durations of pharmacologic ER stress. Xbp1(LKO) and Xbp1(fl/fl) mice showed robust and equal activation of the UPR acutely after induction of ER stress. By 24 h, Xbp1(fl/fl) controls showed complete resolution of UPR activation and no liver injury, indicating successful adaptation to the stress. Conversely, Xbp1(LKO) mice showed ongoing UPR activation associated with progressive liver injury, apoptosis, and, ultimately, fibrosis by day 7 after induction of ER stress. These data indicate that hepatic XBP1 controls the adaptive response of the UPR and is critical to restoring homeostasis in the liver in response to ER stress.
From the Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Shantel
S
Olivares
From the Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 a-henkel2@northwestern.edu.
Anne S
AS
Henkel
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017353:Gene Deletion; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse
JNK; X-box binding protein 1 (XBP1); apoptosis; endoplasmic reticulum stress (ER stress); liver injury; unfolded protein response (UPR)