PMID- 38285890
OWN - NLM
STAT- MEDLINE
DCOM- 20240221
LR  - 20240315
IS  - 2471-254X (Electronic)
IS  - 2471-254X (Linking)
VI  - 8
IP  - 2
DP  - 2024 Feb 1
TI  - Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through 
      lipophagy.
LID - 10.1097/HC9.0000000000000370 [doi]
LID - e0370
AB  - BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by 
      misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the 
      endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic 
      gain-of-function that impacts the endoplasmic reticulum which is theorized to 
      cause liver disease in individuals with AATD who present asymptomatic until 
      late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver 
      disease except liver transplantation. In our study of mitochondrial RNA, we 
      identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. 
      METHODS: Utilizing RNA and protein analysis in an in vitro AATD model, we 
      investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver 
      disease while also characterizing our novel, transgenic AATD mouse model. 
      RESULTS: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In 
      contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT 
      degradation mediated by SIRT3 appeared independent of proteasomal degradation and 
      regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have 
      aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the 
      lipid droplet surface in a direct interaction with Perilipin2, which coats 
      intracellular lipid droplets. SIRT3 overexpression also induced the degradation 
      of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 
      overexpression induces lipophagy by enhancing the interaction of Perilipin2 with 
      HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids 
      through this process. CONCLUSIONS: In this context, SIRT3 activation may 
      eliminate the hepatic toxic gain-of-function associated with the polymerization 
      of ZAAT, providing a rationale for a potential novel therapeutic approach to the 
      treatment of AATD-mediated liver disease.
CI  - Copyright (c) 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on 
      behalf of the American Association for the Study of Liver Diseases.
FAU - Poole, Brittney
AU  - Poole B
AUID- ORCID: 0000-0002-0955-8815
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      University of Florida, Gainesville, Florida, USA.
FAU - Oshins, Regina
AU  - Oshins R
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      University of Florida, Gainesville, Florida, USA.
FAU - Huo, Zhiguang
AU  - Huo Z
AD  - Department of Biostatistics, College of Public Health, University of Florida, 
      Gainesville, Florida, USA.
FAU - Aranyos, Alek
AU  - Aranyos A
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      University of Florida, Gainesville, Florida, USA.
FAU - West, Jesse
AU  - West J
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      University of Florida, Gainesville, Florida, USA.
FAU - Duarte, Sergio
AU  - Duarte S
AD  - Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, 
      University of Florida, Gainesville, Florida, USA.
FAU - Clark, Virginia C
AU  - Clark VC
AUID- ORCID: 0000-0001-6719-3634
AD  - Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, 
      University of Florida, Gainesville, Florida, USA.
FAU - Beduschi, Thiago
AU  - Beduschi T
AD  - Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, 
      University of Florida, Gainesville, Florida, USA.
FAU - Zarrinpar, Ali
AU  - Zarrinpar A
AD  - Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, 
      University of Florida, Gainesville, Florida, USA.
FAU - Brantly, Mark
AU  - Brantly M
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      University of Florida, Gainesville, Florida, USA.
FAU - Khodayari, Nazli
AU  - Khodayari N
AD  - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, 
      University of Florida, Gainesville, Florida, USA.
LA  - eng
PT  - Journal Article
DEP - 20240129
PL  - United States
TA  - Hepatol Commun
JT  - Hepatology communications
JID - 101695860
RN  - 0 (Polymers)
RN  - EC 3.5.1.- (Sirtuin 3)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *alpha 1-Antitrypsin Deficiency/genetics/complications/metabolism
MH  - Autophagy/genetics
MH  - Mice, Transgenic
MH  - Polymers
MH  - *Sirtuin 3/genetics
MH  - Humans
MH  - *alpha 1-Antitrypsin/genetics/metabolism
PMC - PMC10830086
COIS- Virginia Clark consults and received grants from Takeda. She received grants from 
      Arrowhead, Vertex, and Hanmi. The remaining authors have no conflicts to report.
EDAT- 2024/01/29 19:57
MHDA- 2024/01/31 06:42
PMCR- 2024/01/29
CRDT- 2024/01/29 14:23
PHST- 2023/09/13 00:00 [received]
PHST- 2023/12/01 00:00 [accepted]
PHST- 2024/01/31 06:42 [medline]
PHST- 2024/01/29 19:57 [pubmed]
PHST- 2024/01/29 14:23 [entrez]
PHST- 2024/01/29 00:00 [pmc-release]
AID - 02009842-202402010-00012 [pii]
AID - HEP4-23-0789 [pii]
AID - 10.1097/HC9.0000000000000370 [doi]
PST - epublish
SO  - Hepatol Commun. 2024 Jan 29;8(2):e0370. doi: 10.1097/HC9.0000000000000370. 
      eCollection 2024 Feb 1.