PMID- 30615971
OWN - NLM
STAT- MEDLINE
DCOM- 20200406
LR  - 20200408
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 55
DP  - 2019 Mar
TI  - Liver parenchymal cells lacking Lipocalin 2 (LCN2) are prone to endoplasmic 
      reticulum stress and unfolded protein response.
PG  - 90-99
LID - S0898-6568(19)30001-4 [pii]
LID - 10.1016/j.cellsig.2019.01.001 [doi]
AB  - Unfolded protein response (UPR) is an adaptive mechanism allowing the endoplasmic 
      reticulum (ER) to react to an accumulation of unfolded proteins in its lumen, 
      also known as ER stress. The UPR is interconnected with inflammation through 
      several pathways such as reactive oxygen species (ROS) production resulting from 
      the protein folding or alternatively, activation of nuclear factor-kappaB (NF-kappaB) and 
      c-Jun N-terminal kinase (JNK) via IRE1, or induction of acute phase response 
      (APR). Lipocalin 2 (LCN2) is one of the APR proteins induced under inflammatory 
      conditions and up-regulated during ER stress. Upon incubation of Lcn2(-/-) and 
      wild type (wt) primary hepatocytes with tunicamycin (TM) or thapsigargin (TG) we 
      found the Lcn2(-/-) hepatocytes to react with strong UPR to the ER stress, as 
      evidenced by significantly increased levels of Grp94, Bip and Chop mRNA and 
      protein compared to the wt. TM and TG-treated hepatocytes activated p65 NF-kappaB and 
      JNK, the pathways that respond to stress stimuli and playing a central role in 
      inflammation and apoptosis, respectively. ER stress further activated and cleaved 
      full-length CREBH/CREB3L3, the hepatocyte specific transcription factor to induce 
      systemic inflammatory responses. Upregulation of the C/EBP homologous protein 
      (CHOP) was very prominent in Lcn2(-/-) hepatocytes and sustained until 48 h, 
      resulting in hepatocyte apoptosis as evidenced by increased cleaved caspase 3. We 
      also explored the UPR of the Lcn2 null mouse livers in acute intoxication and 
      inflammation stages with a single application of lipopolysaccharide (LPS) or 
      carbon tetrachloride (CCl(4)). The Lcn2 null mice clearly developed stronger UPR 
      in LPS- and CCl(4)-induced ER stress compared to the wt. Our findings indicate 
      that the upregulation of LCN2 during ER stress-induced inflammatory responses 
      protects hepatocytes from being overwhelmed by UPR upon liver injury.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Borkham-Kamphorst, Erawan
AU  - Borkham-Kamphorst E
AD  - Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical 
      Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany. Electronic 
      address: eborkham@ukaachen.de.
FAU - Van de Leur, Eddy
AU  - Van de Leur E
AD  - Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical 
      Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany.
FAU - Haas, Ute
AU  - Haas U
AD  - Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical 
      Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany.
FAU - Weiskirchen, Ralf
AU  - Weiskirchen R
AD  - Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical 
      Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Germany. Electronic 
      address: rweiskirchen@ukaachen.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190104
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Lipocalin-2)
RN  - 0 (Reactive Oxygen Species)
RN  - 126469-30-5 (Lcn2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Endoplasmic Reticulum Stress/*physiology
MH  - Hepatocytes/cytology/*metabolism
MH  - Inflammation/*metabolism
MH  - Lipocalin-2/*physiology
MH  - *Liver/cytology/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Reactive Oxygen Species/metabolism
MH  - Unfolded Protein Response/*physiology
OTO - NOTNLM
OT  - ER stress
OT  - Hepatocytes
OT  - Inflammation
OT  - Lipocalin 2
OT  - Liver
OT  - Unfolded protein response
EDAT- 2019/01/08 06:00
MHDA- 2020/04/09 06:00
CRDT- 2019/01/08 06:00
PHST- 2018/12/13 00:00 [received]
PHST- 2019/01/02 00:00 [revised]
PHST- 2019/01/03 00:00 [accepted]
PHST- 2019/01/08 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/01/08 06:00 [entrez]
AID - S0898-6568(19)30001-4 [pii]
AID - 10.1016/j.cellsig.2019.01.001 [doi]
PST - ppublish
SO  - Cell Signal. 2019 Mar;55:90-99. doi: 10.1016/j.cellsig.2019.01.001. Epub 2019 Jan 
      4.