PMID- 30185770
OWN - NLM
STAT- MEDLINE
DCOM- 20191115
LR  - 20220121
IS  - 2041-4889 (Electronic)
VI  - 9
IP  - 9
DP  - 2018 Sep 5
TI  - Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ 
      HIF-1alpha signaling pathway in liver inflammatory injury.
PG  - 910
LID - 10.1038/s41419-018-0894-1 [doi]
LID - 910
AB  - Activating transcription factor 3 (ATF3) is a stress-induced transcription factor 
      that plays important roles in regulating immune and metabolic homeostasis. 
      Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible 
      factor (HIF) transcription factors are crucial for the regulation of immune cell 
      function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis 
      regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. 
      Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of 
      serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular 
      apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency 
      promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 
      (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1alpha 
      activity, leading to Foxp3 downregulation and RORgammat and IL-17A upregulation in 
      IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone 
      marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1alpha and 
      upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. 
      Silencing of HIF-1alpha in ATF3 KO mice ameliorated IRI-induced liver damage in 
      parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings 
      demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1alpha signaling, which 
      was crucial for the modulation of TLR4-driven inflammatory responses and T cell 
      development. The present study provides potential therapeutic targets for the 
      treatment of liver IRI followed by liver transplantation.
FAU - Zhu, Qiang
AU  - Zhu Q
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China.
AD  - Children's Hospital of Nanjing Medical University, Nanjing, China.
FAU - Wang, Han
AU  - Wang H
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Jiang, Bin
AU  - Jiang B
AD  - Children's Hospital of Nanjing Medical University, Nanjing, China.
FAU - Ni, Xuhao
AU  - Ni X
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Jiang, Longfeng
AU  - Jiang L
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Li, Changyong
AU  - Li C
AD  - Department of Physiology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Wang, Xuehao
AU  - Wang X
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Zhang, Feng
AU  - Zhang F
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China.
FAU - Ke, Bibo
AU  - Ke B
AD  - The Dumont-UCLA Transplant Center, Division of Liver and Pancreas 
      Transplantation, Department of Surgery, David Geffen School of Medicine at 
      University of California-Los Angeles, Los Angeles, CA, USA. bke@mednet.ucla.edu.
FAU - Lu, Ling
AU  - Lu L
AD  - Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical 
      University, Nanjing, China. lvling@njmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180905
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Activating Transcription Factor 3)
RN  - 0 (Atf3 protein, mouse)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Activating Transcription Factor 3/*metabolism
MH  - Animals
MH  - Apoptosis/physiology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Inflammation/*metabolism/pathology
MH  - Liver/metabolism/pathology
MH  - Liver Diseases/*metabolism/pathology
MH  - Macrophages/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neutrophils/metabolism/pathology
MH  - Reperfusion Injury/metabolism/pathology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Up-Regulation/physiology
PMC - PMC6125320
COIS- The authors declare that they have no conflict of interest.
EDAT- 2018/09/07 06:00
MHDA- 2019/11/16 06:00
PMCR- 2018/09/05
CRDT- 2018/09/07 06:00
PHST- 2018/03/09 00:00 [received]
PHST- 2018/07/11 00:00 [accepted]
PHST- 2018/07/10 00:00 [revised]
PHST- 2018/09/07 06:00 [entrez]
PHST- 2018/09/07 06:00 [pubmed]
PHST- 2019/11/16 06:00 [medline]
PHST- 2018/09/05 00:00 [pmc-release]
AID - 10.1038/s41419-018-0894-1 [pii]
AID - 894 [pii]
AID - 10.1038/s41419-018-0894-1 [doi]
PST - epublish
SO  - Cell Death Dis. 2018 Sep 5;9(9):910. doi: 10.1038/s41419-018-0894-1.