PMID- 37060561
OWN - NLM
STAT- MEDLINE
DCOM- 20231006
LR  - 20231010
IS  - 2211-1247 (Electronic)
VI  - 42
IP  - 4
DP  - 2023 Apr 25
TI  - Complementary gene regulation by NRF1 and NRF2 protects against hepatic 
      cholesterol overload.
PG  - 112399
LID - S2211-1247(23)00410-2 [pii]
LID - 10.1016/j.celrep.2023.112399 [doi]
AB  - Hepatic cholesterol overload promotes steatohepatitis. Insufficient understanding 
      of liver stress defense impedes therapy development. Here, we elucidate the role 
      of stress defense transcription factors, nuclear factor erythroid 2 related 
      factor-1 (NRF1) and -2 (NRF2), in counteracting cholesterol-linked liver stress. 
      Using a diet that increases liver cholesterol storage, expression profiles and 
      phenotypes of liver from mice with hepatocyte deficiency of NRF1, NRF2, or both 
      are compared with controls, and chromatin immunoprecipitation sequencing is 
      undertaken to identify target genes. Results show NRF1 and NRF2 co-regulate genes 
      that eliminate cholesterol and mitigate inflammation and oxidative damage. 
      Combined deficiency, but not deficiency of either alone, results in severe 
      steatohepatitis, hepatic cholesterol overload and crystallization, altered bile 
      acid metabolism, and decreased biliary cholesterol. Moreover, therapeutic effects 
      of NRF2-activating drug bardoxolone require NRF1 and are supplemented by NRF1 
      overexpression. Thus, we discover complementary gene programming by NRF1 and NRF2 
      that counteract cholesterol-associated fatty liver disease progression.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Akl, May G
AU  - Akl MG
AD  - Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 
      Saskatoon, SK, Canada; Department of Physiology, Faculty of Medicine, University 
      of Alexandria, Alexandria, Egypt.
FAU - Li, Lei
AU  - Li L
AD  - Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 
      Saskatoon, SK, Canada.
FAU - Baccetto, Raquel
AU  - Baccetto R
AD  - Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 
      Saskatoon, SK, Canada.
FAU - Phanse, Sadhna
AU  - Phanse S
AD  - Department of Chemistry and Biochemistry, University of Regina, Regina, SK, 
      Canada.
FAU - Zhang, Qingzhou
AU  - Zhang Q
AD  - Department of Chemistry and Biochemistry, University of Regina, Regina, SK, 
      Canada.
FAU - Trites, Michael J
AU  - Trites MJ
AD  - Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 
      Saskatoon, SK, Canada.
FAU - McDonald, Sherin
AU  - McDonald S
AD  - Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 
      Saskatoon, SK, Canada.
FAU - Aoki, Hiroyuki
AU  - Aoki H
AD  - Department of Chemistry and Biochemistry, University of Regina, Regina, SK, 
      Canada.
FAU - Babu, Mohan
AU  - Babu M
AD  - Department of Chemistry and Biochemistry, University of Regina, Regina, SK, 
      Canada.
FAU - Widenmaier, Scott B
AU  - Widenmaier SB
AD  - Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 
      Saskatoon, SK, Canada. Electronic address: scott.widenmaier@usask.ca.
LA  - eng
GR  - CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230414
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 97C5T2UQ7J (Cholesterol)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Nrf1 protein, mouse)
SB  - IM
EIN - Cell Rep. 2023 Jul 25;42(7):112872. PMID: 37454293
MH  - Animals
MH  - Mice
MH  - Cholesterol/metabolism
MH  - Gene Expression Regulation
MH  - Liver/metabolism
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - *Non-alcoholic Fatty Liver Disease/metabolism
MH  - Oxidative Stress
OTO - NOTNLM
OT  - CP: Metabolism
OT  - cholesterol
OT  - fatty liver disease
OT  - immunometabolism
OT  - steatohepatitis
OT  - stress defense
OT  - transcription factor
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2023/04/16 06:00
MHDA- 2023/10/04 06:43
CRDT- 2023/04/15 12:36
PHST- 2022/02/10 00:00 [received]
PHST- 2022/10/04 00:00 [revised]
PHST- 2023/03/30 00:00 [accepted]
PHST- 2023/10/04 06:43 [medline]
PHST- 2023/04/16 06:00 [pubmed]
PHST- 2023/04/15 12:36 [entrez]
AID - S2211-1247(23)00410-2 [pii]
AID - 10.1016/j.celrep.2023.112399 [doi]
PST - ppublish
SO  - Cell Rep. 2023 Apr 25;42(4):112399. doi: 10.1016/j.celrep.2023.112399. Epub 2023 
      Apr 14.