Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis.
PNPLA3
autophagy
fatty liver disease
lipid droplet
proteasome
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
07 05 2019
07 05 2019
Historique:
pubmed:
26
4
2019
medline:
17
3
2020
entrez:
26
4
2019
Statut:
ppublish
Résumé
Fatty liver disease (FLD) is a disorder in which accumulation of triglycerides (TGs) in the liver can lead to inflammation, fibrosis, and cirrhosis. Previously, we identified a variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) that is strongly associated with FLD, but the mechanistic basis for the association remains elusive. Although PNPLA3 has TG hydrolase activity in vitro, inactivation or overexpression of the WT protein in mice does not cause steatosis. In contrast, expression of two catalytically defective forms of PNPLA3 (I148M or S47A) in sucrose-fed mice causes accumulation of both PNPLA3 and TGs on hepatic lipid droplets (LDs). To determine if amassing PNPLA3 on LDs is a cause or consequence of steatosis, we engineered a synthetic isoform of PNPLA3 that uncouples protein accumulation from loss of enzymatic activity. Expression of a ubiquitylation-resistant form of PNPLA3 in mice caused accumulation of PNPLA3 on hepatic LDs and development of FLD. Lowering PNPLA3 levels by either shRNA knockdown or proteolysis-targeting chimera (PROTAC)-mediated degradation reduced liver TG content in mice overexpressing PNPLA3(148M). Taken together, our results show that the steatosis associated with PNPLA3(148M) is caused by accumulation of PNPLA3 on LDs.
Identifiants
pubmed: 31019090
pii: 1901974116
doi: 10.1073/pnas.1901974116
pmc: PMC6511016
doi:
Substances chimiques
Triglycerides
0
Sucrose
57-50-1
PNPLA3 protein, mouse
EC 3.1.1.3
Phospholipases A2, Calcium-Independent
EC 3.1.1.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9521-9526Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL020948
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK090066
Pays : United States
Organisme : NIH HHS
ID : S10 OD021684
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
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