PMID- 35804081
OWN - NLM
STAT- MEDLINE
DCOM- 20220712
LR  - 20220915
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Jul 8
TI  - Feedback loop between hepatocyte nuclear factor 1alpha and endoplasmic reticulum 
      stress mitigates liver injury by downregulating hepatocyte apoptosis.
PG  - 11602
LID - 10.1038/s41598-022-15846-8 [doi]
LID - 11602
AB  - Hepatocyte nuclear factor alpha (HNF1alpha), endoplasmic reticulum (ER) stress, and 
      hepatocyte apoptosis contribute to severe acute exacerbation (SAE) of liver 
      injury. Here, we explore HNF1alpha-ER stress-hepatocyte apoptosis interaction in 
      liver injury. LO2, HepG2 and SK-Hep1 cells were treated with thapsigargin (TG) or 
      tunicamycin (TM) to induce ER stress. Carbon tetrachloride (CCl(4)) was used to 
      induce acute liver injury in mice. Low-dose lipopolysaccharide (LPS) exacerbated 
      liver injury in CCl(4)-induced mice. Significant apoptosis, HNF1alpha upregulation, 
      and nuclear factor kappa B (NF-kappaB) activation were observed in human-derived 
      hepatocytes during ER stress. Knockdown of Rela, NF-kappaB p65, inhibited the HNF1alpha 
      upregulation. Following CCl(4) treatment ER stress, apoptosis, HNF1alpha expression 
      and RelA phosphorylation were significantly increased in mice. HNF1alpha knockdown 
      reduced activating transcription factor 4 (ATF4) expression, and aggravated ER 
      stress as well as hepatocyte apoptosis in vivo and in vitro. The double 
      fluorescent reporter gene assay confirmed that HNF1alpha regulated the transcription 
      of ATF4 promoter. LPS aggravated CCl(4)-induced liver injury and reduced HNF1alpha, 
      and ATF4 expression. Therefore, in combination, HNF1alpha and ER stress could be 
      mutually regulated forming a feedback loop, which helps in protecting the injured 
      liver by down-regulating hepatocyte apoptosis. Low-dose LPS aggravates hepatocyte 
      apoptosis and promotes the SAE of liver injury by interfering with the feedback 
      regulation of HNF1alpha and ER stress in acute liver injury.
CI  - (c) 2022. The Author(s).
FAU - Liu, Si-Ying
AU  - Liu SY
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Rao, Jian-Xu
AU  - Rao JX
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Deng, Jie
AU  - Deng J
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Zhang, Gui-Juan
AU  - Zhang GJ
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Jiang, Xiao-Ling
AU  - Jiang XL
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Cheng, Jing
AU  - Cheng J
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Chen, Huan
AU  - Chen H
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China.
FAU - Jiang, Zhi-Gang
AU  - Jiang ZG
AD  - School of Public Health, Zunyi Medical University, Zunyi, 563099, Guizhou, China.
FAU - Xu, De-Lin
AU  - Xu DL
AD  - Cell Biology Department, Zunyi Medical University, Zunyi, 563099, Guizhou, China.
FAU - He, Yi-Huai
AU  - He YH
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, No. 201 Dalian Street, Zunyi, 563000, Guizhou, China. 
      993565989@qq.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220708
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Hepatocyte Nuclear Factor 1-alpha)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 145891-90-3 (Activating Transcription Factor 4)
SB  - IM
MH  - Activating Transcription Factor 4/metabolism
MH  - Animals
MH  - Apoptosis
MH  - *Endoplasmic Reticulum Stress/physiology
MH  - Feedback
MH  - *Hepatocyte Nuclear Factor 1-alpha/metabolism
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Lipopolysaccharides/metabolism
MH  - Liver/metabolism
MH  - Mice
MH  - NF-kappa B/metabolism
PMC - PMC9270423
COIS- The authors declare no competing interests.
EDAT- 2022/07/09 06:00
MHDA- 2022/07/14 06:00
PMCR- 2022/07/08
CRDT- 2022/07/08 23:28
PHST- 2021/08/14 00:00 [received]
PHST- 2022/06/30 00:00 [accepted]
PHST- 2022/07/08 23:28 [entrez]
PHST- 2022/07/09 06:00 [pubmed]
PHST- 2022/07/14 06:00 [medline]
PHST- 2022/07/08 00:00 [pmc-release]
AID - 10.1038/s41598-022-15846-8 [pii]
AID - 15846 [pii]
AID - 10.1038/s41598-022-15846-8 [doi]
PST - epublish
SO  - Sci Rep. 2022 Jul 8;12(1):11602. doi: 10.1038/s41598-022-15846-8.