{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:09Z","timestamp":1787028429844,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T00:00:00Z","timestamp":1595462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB\/TRR57 (projects P13 and Q3)"],"award-info":[{"award-number":["SFB\/TRR57 (projects P13 and Q3)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University","award":["O3-1 and O3-9"],"award-info":[{"award-number":["O3-1 and O3-9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The lack of Lipocalin (LCN2) provokes overwhelming endoplasmic reticulum (ER) stress responses in vitro and in acute toxic liver injury models, resulting in hepatocyte apoptosis. LCN2 is an acute phase protein produced in hepatocytes in response to acute liver injuries. In line with these findings we investigated ER stress responses of Lcn2\u2212\/\u2212 mice in chronic ER stress using a long-term repetitive carbon tetrachloride (CCl4) injection model. We found chronic CCl4 application to enhance ER stress and unfolded protein responses (UPR), including phosphorylation of eukaryotic initiation factor 2\u03b1 (eIF2\u03b1), increased expression of binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (GRP94). IRE1\u03b1\/TRAF2\/JNK signaling enhanced mitochondrial apoptotic pathways, and showed slightly higher in Lcn2\u2212\/\u2212 mice compared to the wild type counterparts, leading to increased hepatocyte apoptosis well evidenced by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Hepatocyte injuries were confirmed by significant high serum alanine transaminase (ALT) levels in CCl4-treated Lcn2\u2212\/\u2212 mice. Lcn2\u2212\/\u2212 mice furthermore developed mild hepatic steatosis, supporting our finding that ER stress promotes lipogenesis. In a previous report we demonstrated that the pharmacological agent tunicamycin (TM) induced ER stress through altered protein glycosylation and induced high amounts of C\/EBP-homologous protein (CHOP), resulting in hepatocyte apoptosis. We compared TM-induced ER stress in wild type, Lcn2\u2212\/\u2212, and Chop null (Chop\u2212\/\u2212) primary hepatocytes and found Chop\u2212\/\u2212 hepatocytes to attenuate ER stress responses and resist ER stress-induced hepatocyte apoptosis through canonical eIF2\u03b1\/GADD34 signaling, inhibiting protein synthesis. Unexpectedly, in later stages of TM incubation, Chop\u2212\/\u2212 hepatocytes resumed activation of IRE1\u03b1\/JNK\/c-Jun and p38\/ATF2 signaling, leading to late hepatocyte apoptosis. This interesting observation indicates Chop\u2212\/\u2212 mice to be unable to absolutely prevent all types of liver injury, while LCN2 protects the hepatocytes by maintaining homeostasis under ER stress conditions.<\/jats:p>","DOI":"10.3390\/ijms21155230","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T11:26:01Z","timestamp":1595503561000},"page":"5230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response"],"prefix":"10.3390","volume":"21","author":[{"given":"Erawan","family":"Borkham-Kamphorst","sequence":"first","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Haas","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Van de Leur","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anothai","family":"Trevanich","sequence":"additional","affiliation":[{"name":"Department of Statistics, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10425","DOI":"10.1016\/S0021-9258(18)82217-7","article-title":"Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase","volume":"268","author":"Kjeldsen","year":"1993","journal-title":"J. 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