PMID- 35301011
OWN - NLM
STAT- MEDLINE
DCOM- 20220627
LR  - 20230703
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 163
IP  - 1
DP  - 2022 Jul
TI  - Regulation of PGC1alpha Downstream of the Insulin Signaling Pathway Plays a Role in 
      the Hepatic Proteotoxicity of Mutant alpha1-Antitrypsin Deficiency Variant Z.
PG  - 270-284
LID - S0016-5085(22)00261-X [pii]
LID - 10.1053/j.gastro.2022.03.010 [doi]
AB  - BACKGROUND & AIMS: Insulin signaling is known to regulate essential proteostasis 
      mechanisms. METHODS: The analyses here examined effects of insulin signaling in 
      the PiZ mouse model of alpha1-antitrypsin deficiency in which hepatocellular 
      accumulation and proteotoxicity of the misfolded alpha1-antitrypsin Z variant (ATZ) 
      causes liver fibrosis and cancer. RESULTS: We first studied the effects of 
      breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with 
      hepatocyte-specific insulin-receptor gene disruption). The results showed 
      decreased hepatic ATZ accumulation and liver fibrosis in PiZ x LIRKO vs PiZ mice, 
      with reversal of those effects when we bred PiZ x LIRKO mice onto a 
      FOXO1-deficient background. Increased intracellular degradation of ATZ mediated 
      by autophagy was identified as the likely mechanism for diminished hepatic 
      proteotoxicity in PiZ x LIRKO mice and the converse was responsible for enhanced 
      toxicity in PiZ x LIRKO x FOXO1-KO animals. Transcriptomic studies showed major 
      effects on oxidative phosphorylation and autophagy genes, and significant 
      induction of peroxisome proliferator-activated-receptor-gamma-coactivator-1alpha (PGC1alpha) 
      expression in PiZ-LIRKO mice. Because PGC1alpha plays a key role in oxidative 
      phosphorylation, we further investigated its effects on ATZ proteostasis in our 
      ATZ-expressing mammalian cell model. The results showed PGC1alpha overexpression or 
      activation enhances autophagic ATZ degradation. CONCLUSIONS: These data implicate 
      suppression of autophagic ATZ degradation by down-regulation of PGC1alpha as one 
      mechanism by which insulin signaling exacerbates hepatic proteotoxicity in PiZ 
      mice, and identify PGC1alpha as a novel target for development of new human 
      alpha1-antitrypsin deficiency liver disease therapies.
CI  - Copyright (c) 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Rudnick, David A
AU  - Rudnick DA
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri; Department of Developmental Biology, Washington University School of 
      Medicine, St Louis, Missouri. Electronic address: rudnick_d@wustl.edu.
FAU - Huang, Jiansheng
AU  - Huang J
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Hidvegi, Tunda
AU  - Hidvegi T
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Chu, Andrew S
AU  - Chu AS
AD  - Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
FAU - Hale, Pamela
AU  - Hale P
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Munanairi, Admire
AU  - Munanairi A
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Dietzen, Dennis J
AU  - Dietzen DJ
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Cliften, Paul F
AU  - Cliften PF
AD  - Department of Genetics, Washington University School of Medicine, St Louis, 
      Missouri; The Genome Technology Access Center, Washington University School of 
      Medicine, St Louis, Missouri.
FAU - Tycksen, Eric
AU  - Tycksen E
AD  - The Genome Technology Access Center, Washington University School of Medicine, St 
      Louis, Missouri.
FAU - Lutkewitte, Andrew J
AU  - Lutkewitte AJ
AD  - Department of Medicine, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Finck, Brian N
AU  - Finck BN
AD  - Department of Medicine, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Pak, Stephen C
AU  - Pak SC
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Silverman, Gary A
AU  - Silverman GA
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri.
FAU - Perlmutter, David H
AU  - Perlmutter DH
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri; Department of Cell Biology, Washington University School of Medicine, 
      St Louis, Missouri.
LA  - eng
GR  - R01 DK131215/DK/NIDDK NIH HHS/United States
GR  - S10 RR027552/RR/NCRR NIH HHS/United States
GR  - P01 DK096990/DK/NIDDK NIH HHS/United States
GR  - P30 CA091842/CA/NCI NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - P30 DK052574/DK/NIDDK NIH HHS/United States
GR  - UL1 TR002345/TR/NCATS NIH HHS/United States
GR  - P30 DK056341/DK/NIDDK NIH HHS/United States
GR  - R01 DK117657/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220315
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Insulin)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
SB  - IM
CIN - Gastroenterology. 2022 Jul;163(1):49-51. PMID: 35500618
MH  - Animals
MH  - *Insulin/metabolism
MH  - *Liver/metabolism/pathology
MH  - Liver Cirrhosis/genetics/metabolism/pathology
MH  - Mammals/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Mutation
MH  - *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/metabolism
MH  - Signal Transduction
MH  - *alpha 1-Antitrypsin Deficiency/genetics/pathology
PMC - PMC9232923
MID - NIHMS1791088
OTO - NOTNLM
OT  - Autophagy
OT  - Liver Disease
OT  - Liver Fibrosis
OT  - Oxidative Phosphorylation
OT  - Proteostasis
COIS- Disclosures: The authors declare no conflicts of interest exist.
EDAT- 2022/03/19 06:00
MHDA- 2022/06/28 06:00
PMCR- 2023/07/01
CRDT- 2022/03/18 05:38
PHST- 2021/09/11 00:00 [received]
PHST- 2022/03/05 00:00 [revised]
PHST- 2022/03/08 00:00 [accepted]
PHST- 2022/03/19 06:00 [pubmed]
PHST- 2022/06/28 06:00 [medline]
PHST- 2022/03/18 05:38 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - S0016-5085(22)00261-X [pii]
AID - 10.1053/j.gastro.2022.03.010 [doi]
PST - ppublish
SO  - Gastroenterology. 2022 Jul;163(1):270-284. doi: 10.1053/j.gastro.2022.03.010. 
      Epub 2022 Mar 15.