PMID- 37625151
OWN - NLM
STAT- MEDLINE
DCOM- 20240319
LR  - 20240320
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 79
IP  - 4
DP  - 2024 Apr 1
TI  - Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease 
      progression.
PG  - 898-911
LID - 10.1097/HEP.0000000000000574 [doi]
AB  - BACKGROUND AND AIMS: Genetic risk factors are major determinants of chronic liver 
      disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 
      (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed 
      PiZ, are major modifiers of metabolic CLD. Both variants are known to affect 
      metabolic CLD through increased endoplasmic reticulum stress, but their combined 
      effect on CLD progression remains largely unknown. Here, we aimed to test our 
      working hypothesis that their combined incidence triggers CLD disease 
      progression. APPROACH AND RESULTS: We showed that patients with PiZZ/PNPLA3 I148M 
      from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the 
      UK Biobank had a trend towards higher liver enzymes, but no increased liver fat 
      accumulation was evident between subgroups. After generating transgenic mice that 
      overexpress the PiZ variant and simultaneously harbor the PNPLA3 I148M knockin 
      (designated as PiZ/PNPLA3 I148M ), we observed that animals with PiZ and 
      PiZ/PNPLA3 I148M showed increased liver enzymes compared to controls during 
      aging. However, no significant difference between PiZ and PiZ/PNPLA3 I148M groups 
      was observed, with no increased liver fat accumulation over time. To further 
      study the impact on CLD progression, a Western-styled diet was administered, 
      which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3 
      I148M livers compared to controls, but the additional presence of PNPLA3 I148M 
      had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3 I148M 
      mice from liver damage and obesity after Western-styled diet feeding. CONCLUSION: 
      Our results demonstrate that the PNPLA3 polymorphism in the absence of additional 
      metabolic risk factors is insufficient to drive the development of advanced liver 
      disease in severe AATD.
CI  - Copyright (c) 2023 American Association for the Study of Liver Diseases.
FAU - Volkert, Ines
AU  - Volkert I
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Fromme, Malin
AU  - Fromme M
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Schneider, Carolin
AU  - Schneider C
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Candels, Lena
AU  - Candels L
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Lindhauer, Cecilia
AU  - Lindhauer C
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Su, Huan
AU  - Su H
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Thorhauge, Katrine
AU  - Thorhauge K
AD  - Department of Gastroenterology and Hepatology, Odense University Hospital, 
      Odense, Denmark.
FAU - Pons, Monica
AU  - Pons M
AD  - Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of 
      Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de 
      Barcelona, Barcelona.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
FAU - Mohamed, Mohamed Ramadan
AU  - Mohamed MR
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Schneider, Kai Markus
AU  - Schneider KM
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Strnad, Pavel
AU  - Strnad P
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Trautwein, Christian
AU  - Trautwein C
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
LA  - eng
PT  - Journal Article
DEP - 20230825
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 3.1.1.4 (Phospholipases A2, Calcium-Independent)
RN  - EC 3.1.1.3 (PNPLA3 protein, mouse)
RN  - EC 3.1.1.3 (PNPLA3 protein, human)
RN  - 0 (Serpina1a protein, mouse)
RN  - 0 (SERPINA1 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Acyltransferases/genetics/metabolism
MH  - *alpha 1-Antitrypsin Deficiency/complications/genetics
MH  - *Digestive System Diseases
MH  - Disease Progression
MH  - Genetic Predisposition to Disease
MH  - Liver/metabolism
MH  - *Non-alcoholic Fatty Liver Disease/metabolism
MH  - Phospholipases A2, Calcium-Independent/genetics/metabolism
MH  - Risk Factors
EDAT- 2023/08/25 18:42
MHDA- 2024/03/19 06:43
CRDT- 2023/08/25 17:12
PHST- 2023/06/01 00:00 [received]
PHST- 2023/07/28 00:00 [accepted]
PHST- 2024/03/19 06:43 [medline]
PHST- 2023/08/25 18:42 [pubmed]
PHST- 2023/08/25 17:12 [entrez]
AID - 01515467-990000000-00549 [pii]
AID - 10.1097/HEP.0000000000000574 [doi]
PST - ppublish
SO  - Hepatology. 2024 Apr 1;79(4):898-911. doi: 10.1097/HEP.0000000000000574. Epub 
      2023 Aug 25.