PMID- 29782848
OWN - NLM
STAT- MEDLINE
DCOM- 20180914
LR  - 20211204
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 155
IP  - 3
DP  - 2018 Sep
TI  - Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic 
      Ethanol-Induced Liver Injury and Steatosis in Mice.
PG  - 865-879.e12
LID - S0016-5085(18)34560-8 [pii]
LID - 10.1053/j.gastro.2018.05.027 [doi]
AB  - BACKGROUND & AIMS: Defects in lysosome function and autophagy contribute to the 
      pathogenesis of alcoholic liver disease. We investigated the mechanisms by which 
      alcohol consumption affects these processes by evaluating the functions of 
      transcription factor EB (TFEB), which regulates lysosomal biogenesis. METHODS: We 
      performed studies with GFP-LC3 mice, mice with liver-specific deletion of TFEB, 
      mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), 
      mice with disruption of the Tefb and Tfe3 genes (TFEB and TFE3 double-knockout 
      mice), and Tfeb(flox/flox) albumin cre-negative mice (controls). TFEB was 
      overexpressed from adenoviral vectors or knocked down with small interfering RNAs 
      in mouse livers. Mice were placed on diets of regular ethanol feeding plus an 
      acute binge to induce liver damage (ethanol diet); some mice also were given 
      injections of torin-1, an inhibitor of the kinase activity of the mechanistic 
      target of rapamycin (mTOR). Liver tissues were collected and analyzed by 
      immunohistochemistry, immunoblots, and quantitative real-time polymerase chain 
      reaction to monitor lysosome biogenesis. We analyzed levels of TFEB in liver 
      tissues from patients with alcoholic hepatitis and from healthy donors (controls) 
      by immunohistochemistry. RESULTS: Liver tissues from mice on the ethanol diet had 
      lower levels of total and nuclear TFEB compared with control mice, and 
      hepatocytes had decreased lysosome biogenesis and autophagy. Hepatocytes from 
      mice on the ethanol diet had increased translocation of mTOR into lysosomes, 
      resulting in increased mTOR activation. Administration of torin-1 increased liver 
      levels of TFEB and decreased steatosis and liver injury induced by ethanol. Mice 
      that overexpressed TFEB in the liver developed less severe ethanol-induced liver 
      injury and had increased lysosomal biogenesis and mitochondrial bioenergetics 
      compared with mice carrying a control vector. Mice with knockdown of TFEB and 
      TFEB-TFE3 double-knockout mice developed more severe liver injury in response to 
      the ethanol diet than control mice. Liver tissues from patients with 
      alcohol-induced hepatitis had lower nuclear levels of TFEB than control tissues. 
      CONCLUSIONS: We found that ethanol feeding plus an acute binge decreased hepatic 
      expression of TFEB, which is required for lysosomal biogenesis and autophagy. 
      Strategies to block mTOR activity or increase levels of TFEB might be developed 
      to protect the liver from ethanol-induced damage.
CI  - Copyright (c) 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Chao, Xiaojuan
AU  - Chao X
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Wang, Shaogui
AU  - Wang S
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Zhao, Katrina
AU  - Zhao K
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Li, Yuan
AU  - Li Y
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Williams, Jessica A
AU  - Williams JA
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Li, Tiangang
AU  - Li T
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Chavan, Hemantkumar
AU  - Chavan H
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Krishnamurthy, Partha
AU  - Krishnamurthy P
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - He, Xi C
AU  - He XC
AD  - Stowers Institute for Medical Research, Kansas City, Missouri; Department of 
      Pathology, University of Kansas Medical Center, Kansas City, Kansas.
FAU - Li, Linheng
AU  - Li L
AD  - Stowers Institute for Medical Research, Kansas City, Missouri; Department of 
      Pathology, University of Kansas Medical Center, Kansas City, Kansas.
FAU - Ballabio, Andrea
AU  - Ballabio A
AD  - Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy; 
      Medical Genetics, Department of Translational Medicine, Federico II University, 
      Naples, Italy; Department of Molecular and Human Genetics, Baylor College of 
      Medicine, Houston, Texas.
FAU - Ni, Hong-Min
AU  - Ni HM
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas.
FAU - Ding, Wen-Xing
AU  - Ding WX
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, Kansas. Electronic address: wxding@kumc.edu.
LA  - eng
GR  - R01 DK102487/DK/NIDDK NIH HHS/United States
GR  - P20 GM104936/GM/NIGMS NIH HHS/United States
GR  - R01 AA020518/AA/NIAAA NIH HHS/United States
GR  - P30 GM118247/GM/NIGMS NIH HHS/United States
GR  - R37 AA020518/AA/NIAAA NIH HHS/United States
GR  - U01 AA024733/AA/NIAAA NIH HHS/United States
GR  - R01 DK102142/DK/NIDDK NIH HHS/United States
GR  - P20 GM103549/GM/NIGMS NIH HHS/United States
GR  - R24 AA025017/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180518
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (Tcfeb protein, mouse)
RN  - 3K9958V90M (Ethanol)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Autophagy. 2018;14(9):1646-1648. PMID: 29969942
CIN - Dig Med Res. 2018 Sep;1:. PMID: 30450489
MH  - Animals
MH  - Autophagy/*genetics
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*physiology
MH  - Ethanol
MH  - Fatty Liver/*genetics
MH  - Hepatocytes/physiology
MH  - Liver/metabolism
MH  - Liver Diseases, Alcoholic/*genetics
MH  - Lysosomes/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Organelle Biogenesis
MH  - TOR Serine-Threonine Kinases/physiology
PMC - PMC6120772
MID - NIHMS969105
OTO - NOTNLM
OT  - Fatty Liver
OT  - Gene Regulation
OT  - Hepatic Protection
OT  - Mouse Model
COIS- Conflict of Interest: These authors declare that they have nothing to disclose.
EDAT- 2018/05/22 06:00
MHDA- 2018/09/15 06:00
PMCR- 2019/09/01
CRDT- 2018/05/22 06:00
PHST- 2018/01/09 00:00 [received]
PHST- 2018/04/16 00:00 [revised]
PHST- 2018/05/10 00:00 [accepted]
PHST- 2018/05/22 06:00 [pubmed]
PHST- 2018/09/15 06:00 [medline]
PHST- 2018/05/22 06:00 [entrez]
PHST- 2019/09/01 00:00 [pmc-release]
AID - S0016-5085(18)34560-8 [pii]
AID - 10.1053/j.gastro.2018.05.027 [doi]
PST - ppublish
SO  - Gastroenterology. 2018 Sep;155(3):865-879.e12. doi: 10.1053/j.gastro.2018.05.027. 
      Epub 2018 May 18.