PMID- 32738395
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20210618
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 159
DP  - 2020 Nov 1
TI  - Alcohol-induced CYP2E1, mitochondrial dynamics and retrograde signaling in human 
      hepatic 3D organoids.
PG  - 1-14
LID - S0891-5849(20)31127-8 [pii]
LID - 10.1016/j.freeradbiomed.2020.06.030 [doi]
AB  - Alcohol toxicity is a significant health problem with ~3 million estimated deaths 
      per year globally. Alcohol is metabolized to the toxic metabolite, acetaldehyde 
      by alcohol dehydrogenase or CYP2E1 in the hepatic tissue, and also induces 
      reactive oxygen species (ROS), which together play a pivotal role in cell and 
      tissue damage. Our previous studies with COS-7 cells transduced with unique human 
      CYP2E1 variants that mostly localize to either microsomes or mitochondria 
      revealed that mitochondrially-localized CYP2E1 drives alcohol toxicity through 
      the generation of higher levels of ROS, which has a consequent effect on 
      cytochrome c oxidase (CcO) and mitochondrial oxidative function. Alcohol 
      treatment of human hepatocyte cell line, HepaRG, in monolayer cultures increased 
      ROS, affected CcO activity/stability, and induced mitophagy. Alcohol treatment of 
      3D organoids of HepaRG cells induced higher levels of CYP2E1 mRNA and activated 
      mitochondrial stress-induced retrograde signaling, and also induced markers of 
      hepatic steatosis. Knock down of CYP2E1 mRNA using specific shRNA, FK506, a 
      Calcineurin inhibitor, and Mdivi-1, a DRP1 inhibitor, ameliorated alcohol-induced 
      mitochondrial retrograde signaling, and hepatic steatosis. These results for the 
      first time present a mechanistic link between CYP2E1 function and alcohol 
      mediated mitochondrial dysfunction, retrograde signaling, and activation of 
      hepatic steatosis in a 3D organoid system that closely recapitulates the in vivo 
      liver response.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Angireddy, Rajesh
AU  - Angireddy R
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, 3800 Spruce 
      Street, University of Pennsylvania, Philadelphia, PA, 19104, USA.
FAU - Chowdhury, Anindya Roy
AU  - Chowdhury AR
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, 3800 Spruce 
      Street, University of Pennsylvania, Philadelphia, PA, 19104, USA.
FAU - Zielonka, Jacek
AU  - Zielonka J
AD  - Department of Biophysics and, Free Radical Research Center, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
FAU - Ruthel, Gordon
AU  - Ruthel G
AD  - Department of Pathobiology, Veterinary Center for Imaging, Hill Pavilion, School 
      of Veterinary Medicine, University of Pennsylvania, PA, 19104, USA.
FAU - Kalyanaraman, Balaraman
AU  - Kalyanaraman B
AD  - Department of Biophysics and, Free Radical Research Center, Medical College of 
      Wisconsin, Milwaukee, WI, USA.
FAU - Avadhani, Narayan G
AU  - Avadhani NG
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, 3800 Spruce 
      Street, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic 
      address: narayan@vet.upenn.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200729
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - EC 1.14.13.- (Cytochrome P-450 CYP2E1)
SB  - IM
MH  - *Cytochrome P-450 CYP2E1/genetics/metabolism
MH  - Humans
MH  - Liver/metabolism
MH  - *Mitochondrial Dynamics
MH  - Organoids/metabolism
MH  - Oxidative Stress
OTO - NOTNLM
OT  - CYP2E1
OT  - Organoids
OT  - Reactive oxygen species
OT  - Retrograde signaling
OT  - Steatosis
COIS- Declaration of competing interest The authors declare that they have no conflict 
      of interest with the contents of this article.
EDAT- 2020/08/02 06:00
MHDA- 2021/06/22 06:00
CRDT- 2020/08/02 06:00
PHST- 2020/02/26 00:00 [received]
PHST- 2020/06/19 00:00 [revised]
PHST- 2020/06/21 00:00 [accepted]
PHST- 2020/08/02 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/08/02 06:00 [entrez]
AID - S0891-5849(20)31127-8 [pii]
AID - 10.1016/j.freeradbiomed.2020.06.030 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2020 Nov 1;159:1-14. doi: 
      10.1016/j.freeradbiomed.2020.06.030. Epub 2020 Jul 29.