Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure.
Acetaminophen
/ toxicity
Adult
Animals
Chemical and Drug Induced Liver Injury
/ etiology
Disease Models, Animal
Drug Overdose
/ complications
Endoplasmic Reticulum Stress
/ drug effects
Hepatocytes
/ drug effects
Humans
Lipogenesis
/ drug effects
Liver
/ cytology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phosphoproteins
/ genetics
Steroids
/ metabolism
Transplantation Chimera
Up-Regulation
Valproic Acid
/ administration & dosage
APAP Toxicity
Lipid
Mouse Model
Signal Transduction
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
17
07
2018
revised:
11
04
2019
accepted:
20
04
2019
pubmed:
29
4
2019
medline:
27
8
2019
entrez:
29
4
2019
Statut:
ppublish
Résumé
Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1 Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1 In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.
Sections du résumé
BACKGROUND & AIMS
Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis.
METHODS
Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1
RESULTS
Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1
CONCLUSIONS
In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.
Identifiants
pubmed: 31029706
pii: S0016-5085(19)36716-2
doi: 10.1053/j.gastro.2019.04.023
pii:
doi:
Substances chimiques
Phosphoproteins
0
Steroids
0
steroidogenic acute regulatory protein
0
Acetaminophen
362O9ITL9D
Valproic Acid
614OI1Z5WI
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
552-568Subventions
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.