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Article

Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response

1
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany
2
Department of Statistics, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(15), 5230; https://doi.org/10.3390/ijms21155230
Received: 18 June 2020 / Revised: 16 July 2020 / Accepted: 21 July 2020 / Published: 23 July 2020
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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−/− 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 2α (eIF2α), increased expression of binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (GRP94). IRE1α/TRAF2/JNK signaling enhanced mitochondrial apoptotic pathways, and showed slightly higher in Lcn2−/− 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−/− mice. Lcn2−/− 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−/−, and Chop null (Chop−/−) primary hepatocytes and found Chop−/− hepatocytes to attenuate ER stress responses and resist ER stress-induced hepatocyte apoptosis through canonical eIF2α/GADD34 signaling, inhibiting protein synthesis. Unexpectedly, in later stages of TM incubation, Chop−/− hepatocytes resumed activation of IRE1α/JNK/c-Jun and p38/ATF2 signaling, leading to late hepatocyte apoptosis. This interesting observation indicates Chop−/− mice to be unable to absolutely prevent all types of liver injury, while LCN2 protects the hepatocytes by maintaining homeostasis under ER stress conditions. View Full-Text
Keywords: ER stress; UPR; LCN2; CHOP; hepatocyte; apoptosis ER stress; UPR; LCN2; CHOP; hepatocyte; apoptosis
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MDPI and ACS Style

Borkham-Kamphorst, E.; Haas, U.; Van de Leur, E.; Trevanich, A.; Weiskirchen, R. Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response. Int. J. Mol. Sci. 2020, 21, 5230. https://doi.org/10.3390/ijms21155230

AMA Style

Borkham-Kamphorst E, Haas U, Van de Leur E, Trevanich A, Weiskirchen R. Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response. International Journal of Molecular Sciences. 2020; 21(15):5230. https://doi.org/10.3390/ijms21155230

Chicago/Turabian Style

Borkham-Kamphorst, Erawan, Ute Haas, Eddy Van de Leur, Anothai Trevanich, and Ralf Weiskirchen. 2020. "Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response" International Journal of Molecular Sciences 21, no. 15: 5230. https://doi.org/10.3390/ijms21155230

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