PMID- 37584647
OWN - NLM
STAT- MEDLINE
DCOM- 20230817
LR  - 20230829
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 37
IP  - 9
DP  - 2023 Sep
TI  - HIF-1alpha inhibition in macrophages preserves acute liver failure by reducing IL-1beta 
      production.
PG  - e23140
LID - 10.1096/fj.202300428RR [doi]
AB  - The development of acute liver failure (ALF) is dependent on its local inducer. 
      Inflammation is a high-frequency and critical factor that accelerates hepatocyte 
      death and liver failure. In response to injury stress, the expression of the 
      transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in macrophages is 
      promoted by both oxygen-dependent and oxygen-independent mechanisms, thus 
      promoting the expression and secretion of the cytokine interleukin-1beta (IL-1beta). 
      IL-1beta further induces hepatocyte apoptosis or necrosis by signaling through the 
      receptor (IL-1R) on hepatocyte. HIF-1alpha knockout in macrophages or IL-1R knockout 
      in hepatocytes protects against liver failure. However, whether HIF-1alpha inhibition 
      in macrophages has a protective role in ALF is unclear. In this study, we 
      revealed that the small molecule HIF-1alpha inhibitor PX-478 inhibits the expression 
      and secretion of IL-1beta, but not tumor necrosis factor alpha (TNFalpha), in bone 
      marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury 
      in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. 
      In addition, preventive or therapeutic administration of PX-478 combined with 
      TNFalpha neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken 
      together, our data suggest that PX-478 administration leads to HIF-1alpha inhibition 
      and decreased IL-1beta secretion in macrophages, which represents a promising 
      therapeutic strategy for inflammation-induced ALF.
CI  - (c) 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on 
      behalf of Federation of American Societies for Experimental Biology.
FAU - Kong, Xiangrong
AU  - Kong X
AUID- ORCID: 0009-0002-1755-8513
AD  - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 
      Nanjing, P.R. China.
FAU - Liu, Wei
AU  - Liu W
AUID- ORCID: 0009-0005-3670-8718
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
AD  - University of Chinese Academy of Sciences, Beijing, P.R. China.
FAU - Zhang, Xinwen
AU  - Zhang X
AUID- ORCID: 0009-0003-6912-8002
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
FAU - Zhou, Chendong
AU  - Zhou C
AUID- ORCID: 0009-0005-1370-0051
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
FAU - Sun, Xinyu
AU  - Sun X
AUID- ORCID: 0009-0009-5611-2988
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
FAU - Cheng, Long
AU  - Cheng L
AUID- ORCID: 0009-0002-3865-9890
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
AD  - University of Chinese Academy of Sciences, Beijing, P.R. China.
FAU - Lin, Jinxia
AU  - Lin J
AUID- ORCID: 0009-0002-6316-0995
AD  - Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd, Zhangzhou, P.R. China.
FAU - Xie, Zhifu
AU  - Xie Z
AUID- ORCID: 0009-0005-3364-0287
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
FAU - Li, Jingya
AU  - Li J
AUID- ORCID: 0000-0003-3457-8153
AD  - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 
      Nanjing, P.R. China.
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. 
      China.
AD  - University of Chinese Academy of Sciences, Beijing, P.R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Tumor Necrosis Factor-alpha/metabolism
MH  - Lipopolysaccharides/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - *Liver Failure, Acute/chemically induced/pathology
MH  - Macrophages/metabolism
MH  - Inflammation/metabolism
MH  - Necrosis/metabolism
MH  - Oxygen/metabolism
OTO - NOTNLM
OT  - HIF-1alpha inhibitor
OT  - acute liver failure
OT  - cell death
OT  - interleukin-1beta
OT  - macrophage
EDAT- 2023/08/16 12:42
MHDA- 2023/08/17 06:43
CRDT- 2023/08/16 10:42
PHST- 2023/07/13 00:00 [revised]
PHST- 2023/03/07 00:00 [received]
PHST- 2023/08/01 00:00 [accepted]
PHST- 2023/08/17 06:43 [medline]
PHST- 2023/08/16 12:42 [pubmed]
PHST- 2023/08/16 10:42 [entrez]
AID - 10.1096/fj.202300428RR [doi]
PST - ppublish
SO  - FASEB J. 2023 Sep;37(9):e23140. doi: 10.1096/fj.202300428RR.