Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis.

Animals Apoptosis Autophagosomes / ultrastructure Autophagy / drug effects Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism Benzylamines / pharmacology Cell Survival Copper / toxicity Copper-Transporting ATPases / genetics Female Hep G2 Cells Hepatocytes / physiology Hepatolenticular Degeneration / physiopathology Humans Liver / physiopathology Male Mice Mice, Knockout Microscopy, Confocal Microscopy, Electron Mitochondria / ultrastructure Protein Transport Quinazolines / pharmacology Rats Signal Transduction TOR Serine-Threonine Kinases / metabolism

Copper Copper Homeostasis Metal Toxicity Mitophagy

Journal

Gastroenterology

ISSN: 1528-0012

Titre abrégé: Gastroenterology

Pays: United States

ID NLM: 0374630

Informations de publication

Date de publication:
03 2019

Historique:

received: 14 03 2018

revised: 23 10 2018

accepted: 10 11 2018

pubmed: 20 11 2018

medline: 4 4 2019

entrez: 20 11 2018

Statut: ppublish

Résumé

Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase copper transporting β gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD. We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD.

Sections du résumé

BACKGROUND & AIMS

METHODS

We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b

RESULTS

After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b

CONCLUSION

ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD.

Identifiants

DOI: 10.1053/j.gastro.2018.11.032 PMID: 30452922

pubmed: 30452922

pii: S0016-5085(18)35280-6

doi: 10.1053/j.gastro.2018.11.032

pii:

doi:

Substances chimiques

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors 0

Benzylamines 0

Quinazolines 0

TFEB protein, rat 0

Tcfeb protein, mouse 0

spautin-1 0

Copper 789U1901C5

TOR Serine-Threonine Kinases EC 2.7.11.1

ATP7B protein, human EC 7.2.2.8

Atp7b protein, mouse EC 7.2.2.8

Atp7b protein, rat EC 7.2.2.8

Copper-Transporting ATPases EC 7.2.2.8

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1173-1189.e5