Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD.
NAFLD
chaperone-mediated autophagy
lipolysis
perilipin 5
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
19
01
2020
revised:
26
03
2020
accepted:
06
04
2020
pubmed:
28
4
2020
medline:
22
6
2021
entrez:
28
4
2020
Statut:
ppublish
Résumé
The pathological hallmark of nonalcoholic fatty liver disease (NAFLD) is an imbalance in hepatic lipid homeostasis, in which lipophagy has been found to play a vital role. However, the underlying molecular mechanisms remain unclear. We investigated the role of chaperone-mediated autophagy (CMA) in the pathogenesis of NAFLD. CMA activity was evaluated in liver tissues from NAFLD patients and high-fat diet (HFD)-fed mice. Liver-specific LAMP2A-knockout mice and HepG2 cells lacking LAMP2A [L2A(-) cells] were used to investigate the influence of CMA on lipolysis in hepatocytes. The expression of Plin5, a lipid droplet (LD)-related protein, was also evaluated in human and mouse liver tissues and in [L2A(-)] cells. Here, we found disrupted CMA function in the livers of NAFLD patients and animal models, displaying obvious reduction of LAMP2A and concurrent with decreased levels of CMA-positive regulators. More LDs and higher serum triglycerides accumulated in liver-specific LAMP2A-knockout mice and L2A(-) cells under high-fat challenge. Meanwhile, deleting LAMP2A hindered LD breakdown but not increased LD formation. In addition, the LD-associated protein Plin5 is a CMA substrate, and its degradation through CMA is required for LD breakdown. We propose that the disruption of CMA-induced Plin5 degradation obstacles LD breakdown, explaining the lipid homeostasis imbalance in NAFLD.
Sections du résumé
BACKGROUND & AIMS
The pathological hallmark of nonalcoholic fatty liver disease (NAFLD) is an imbalance in hepatic lipid homeostasis, in which lipophagy has been found to play a vital role. However, the underlying molecular mechanisms remain unclear. We investigated the role of chaperone-mediated autophagy (CMA) in the pathogenesis of NAFLD.
METHODS
CMA activity was evaluated in liver tissues from NAFLD patients and high-fat diet (HFD)-fed mice. Liver-specific LAMP2A-knockout mice and HepG2 cells lacking LAMP2A [L2A(-) cells] were used to investigate the influence of CMA on lipolysis in hepatocytes. The expression of Plin5, a lipid droplet (LD)-related protein, was also evaluated in human and mouse liver tissues and in [L2A(-)] cells.
RESULTS
Here, we found disrupted CMA function in the livers of NAFLD patients and animal models, displaying obvious reduction of LAMP2A and concurrent with decreased levels of CMA-positive regulators. More LDs and higher serum triglycerides accumulated in liver-specific LAMP2A-knockout mice and L2A(-) cells under high-fat challenge. Meanwhile, deleting LAMP2A hindered LD breakdown but not increased LD formation. In addition, the LD-associated protein Plin5 is a CMA substrate, and its degradation through CMA is required for LD breakdown.
CONCLUSIONS
We propose that the disruption of CMA-induced Plin5 degradation obstacles LD breakdown, explaining the lipid homeostasis imbalance in NAFLD.
Substances chimiques
Lipids
0
Perilipin-5
0
Plin5 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2427-2438Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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