Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

Sandra Torres, Anna Baulies, N. Insausti-Urkia, Cristina Alarcón-Vila, Raquel Fucho, E. Solsona-Vilarrasa, Susana Núñez, D. Robles, Vicent Ribas, Leslie Wakefield, Markus Grompe, M. Isabel Lucena, Raul J. Andrade, S. Win, T. A. Aung, Neil Kaplowitz, Carmen García-Ruiz, Jose C. Fernández-Checa

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah−/−/Rag2−/−/Il2rg−/−/NOD (FRGN) mice to create mice with humanized livers. 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. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. 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.

Original languageEnglish (US)
Pages (from-to)552-568
Number of pages17
JournalGastroenterology
Volume157
Issue number2
DOIs
StatePublished - Aug 1 2019

Fingerprint

Endoplasmic Reticulum Stress
Acute Liver Failure
Acetaminophen
Up-Regulation
Valproic Acid
Liver
Glutathione
Inbred NOD Mouse
JNK Mitogen-Activated Protein Kinases
Cholesterol
Phosphorylation
Cytochrome P-450 CYP2E1
Acetylcysteine
Inbred C57BL Mouse

Keywords

  • APAP Toxicity
  • Lipid
  • Mouse Model
  • Signal Transduction

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Torres, S., Baulies, A., Insausti-Urkia, N., Alarcón-Vila, C., Fucho, R., Solsona-Vilarrasa, E., ... Fernández-Checa, J. C. (2019). Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure. Gastroenterology, 157(2), 552-568. https://doi.org/10.1053/j.gastro.2019.04.023

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure. / Torres, Sandra; Baulies, Anna; Insausti-Urkia, N.; Alarcón-Vila, Cristina; Fucho, Raquel; Solsona-Vilarrasa, E.; Núñez, Susana; Robles, D.; Ribas, Vicent; Wakefield, Leslie; Grompe, Markus; Lucena, M. Isabel; Andrade, Raul J.; Win, S.; Aung, T. A.; Kaplowitz, Neil; García-Ruiz, Carmen; Fernández-Checa, Jose C.

In: Gastroenterology, Vol. 157, No. 2, 01.08.2019, p. 552-568.

Research output: Contribution to journalArticle

Torres, S, Baulies, A, Insausti-Urkia, N, Alarcón-Vila, C, Fucho, R, Solsona-Vilarrasa, E, Núñez, S, Robles, D, Ribas, V, Wakefield, L, Grompe, M, Lucena, MI, Andrade, RJ, Win, S, Aung, TA, Kaplowitz, N, García-Ruiz, C & Fernández-Checa, JC 2019, 'Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure', Gastroenterology, vol. 157, no. 2, pp. 552-568. https://doi.org/10.1053/j.gastro.2019.04.023
Torres S, Baulies A, Insausti-Urkia N, Alarcón-Vila C, Fucho R, Solsona-Vilarrasa E et al. Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure. Gastroenterology. 2019 Aug 1;157(2):552-568. https://doi.org/10.1053/j.gastro.2019.04.023
Torres, Sandra ; Baulies, Anna ; Insausti-Urkia, N. ; Alarcón-Vila, Cristina ; Fucho, Raquel ; Solsona-Vilarrasa, E. ; Núñez, Susana ; Robles, D. ; Ribas, Vicent ; Wakefield, Leslie ; Grompe, Markus ; Lucena, M. Isabel ; Andrade, Raul J. ; Win, S. ; Aung, T. A. ; Kaplowitz, Neil ; García-Ruiz, Carmen ; Fernández-Checa, Jose C. / Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure. In: Gastroenterology. 2019 ; Vol. 157, No. 2. pp. 552-568.
@article{7cdbce0b72d64da799a5a6110a6353a0,
title = "Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure",
abstract = "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 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah−/−/Rag2−/−/Il2rg−/−/NOD (FRGN) mice to create mice with humanized livers. 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. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. 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.",
keywords = "APAP Toxicity, Lipid, Mouse Model, Signal Transduction",
author = "Sandra Torres and Anna Baulies and N. Insausti-Urkia and Cristina Alarc{\'o}n-Vila and Raquel Fucho and E. Solsona-Vilarrasa and Susana N{\'u}{\~n}ez and D. Robles and Vicent Ribas and Leslie Wakefield and Markus Grompe and Lucena, {M. Isabel} and Andrade, {Raul J.} and S. Win and Aung, {T. A.} and Neil Kaplowitz and Carmen Garc{\'i}a-Ruiz and Fern{\'a}ndez-Checa, {Jose C.}",
year = "2019",
month = "8",
day = "1",
doi = "10.1053/j.gastro.2019.04.023",
language = "English (US)",
volume = "157",
pages = "552--568",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

TY - JOUR

T1 - Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

AU - Torres, Sandra

AU - Baulies, Anna

AU - Insausti-Urkia, N.

AU - Alarcón-Vila, Cristina

AU - Fucho, Raquel

AU - Solsona-Vilarrasa, E.

AU - Núñez, Susana

AU - Robles, D.

AU - Ribas, Vicent

AU - Wakefield, Leslie

AU - Grompe, Markus

AU - Lucena, M. Isabel

AU - Andrade, Raul J.

AU - Win, S.

AU - Aung, T. A.

AU - Kaplowitz, Neil

AU - García-Ruiz, Carmen

AU - Fernández-Checa, Jose C.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah−/−/Rag2−/−/Il2rg−/−/NOD (FRGN) mice to create mice with humanized livers. 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. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. 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.

AB - 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 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah−/−/Rag2−/−/Il2rg−/−/NOD (FRGN) mice to create mice with humanized livers. 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. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. 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.

KW - APAP Toxicity

KW - Lipid

KW - Mouse Model

KW - Signal Transduction

UR - http://www.scopus.com/inward/record.url?scp=85069611505&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069611505&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2019.04.023

DO - 10.1053/j.gastro.2019.04.023

M3 - Article

C2 - 31029706

AN - SCOPUS:85069611505

VL - 157

SP - 552

EP - 568

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -