Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

Bharat Jaishy, Quanjiang Zhang, Heaseung S. Chung, Christian Riehle, Jamie Soto, Stephen Jenkins, Patrick Abel, L. Ashley Cowart, Jennifer E. Van Eyk, E. Dale Abel

Research output: Contribution to journalArticle

Abstract

Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKCβII. These findings reveal a novel mechanism linking lipotoxicity with a PKCβ-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.

Original languageEnglish (US)
Pages (from-to)546-561
Number of pages16
JournalJournal of Lipid Research
Volume56
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Palmitates
Enzyme activity
Cardiac Myocytes
Autophagy
Chemical activation
Fluxes
Lipids
Acidification
Enzymes
Superoxides
Protein Kinases
Obesity
Enzyme inhibition
NADPH Oxidase
Lysosomes
Organelles
Homeostasis
Fatty Acids
Fats
Autophagosomes

Keywords

  • Autophagy
  • Cardiomyocytes
  • Fatty acids
  • Lysosomes
  • NADPH oxidase 2
  • Protein kinase Cβ

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Jaishy, B., Zhang, Q., Chung, H. S., Riehle, C., Soto, J., Jenkins, S., ... Abel, E. D. (2015). Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. Journal of Lipid Research, 56(3), 546-561. https://doi.org/10.1194/jlr.M055152

Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. / Jaishy, Bharat; Zhang, Quanjiang; Chung, Heaseung S.; Riehle, Christian; Soto, Jamie; Jenkins, Stephen; Abel, Patrick; Cowart, L. Ashley; Van Eyk, Jennifer E.; Abel, E. Dale.

In: Journal of Lipid Research, Vol. 56, No. 3, 01.03.2015, p. 546-561.

Research output: Contribution to journalArticle

Jaishy, B, Zhang, Q, Chung, HS, Riehle, C, Soto, J, Jenkins, S, Abel, P, Cowart, LA, Van Eyk, JE & Abel, ED 2015, 'Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity', Journal of Lipid Research, vol. 56, no. 3, pp. 546-561. https://doi.org/10.1194/jlr.M055152
Jaishy, Bharat ; Zhang, Quanjiang ; Chung, Heaseung S. ; Riehle, Christian ; Soto, Jamie ; Jenkins, Stephen ; Abel, Patrick ; Cowart, L. Ashley ; Van Eyk, Jennifer E. ; Abel, E. Dale. / Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. In: Journal of Lipid Research. 2015 ; Vol. 56, No. 3. pp. 546-561.
@article{43a5dff658ea4d9faf77d1a580230378,
title = "Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity",
abstract = "Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKCβII. These findings reveal a novel mechanism linking lipotoxicity with a PKCβ-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.",
keywords = "Autophagy, Cardiomyocytes, Fatty acids, Lysosomes, NADPH oxidase 2, Protein kinase Cβ",
author = "Bharat Jaishy and Quanjiang Zhang and Chung, {Heaseung S.} and Christian Riehle and Jamie Soto and Stephen Jenkins and Patrick Abel and Cowart, {L. Ashley} and {Van Eyk}, {Jennifer E.} and Abel, {E. Dale}",
year = "2015",
month = "3",
day = "1",
doi = "10.1194/jlr.M055152",
language = "English (US)",
volume = "56",
pages = "546--561",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

TY - JOUR

T1 - Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

AU - Jaishy, Bharat

AU - Zhang, Quanjiang

AU - Chung, Heaseung S.

AU - Riehle, Christian

AU - Soto, Jamie

AU - Jenkins, Stephen

AU - Abel, Patrick

AU - Cowart, L. Ashley

AU - Van Eyk, Jennifer E.

AU - Abel, E. Dale

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKCβII. These findings reveal a novel mechanism linking lipotoxicity with a PKCβ-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.

AB - Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKCβII. These findings reveal a novel mechanism linking lipotoxicity with a PKCβ-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.

KW - Autophagy

KW - Cardiomyocytes

KW - Fatty acids

KW - Lysosomes

KW - NADPH oxidase 2

KW - Protein kinase Cβ

UR - http://www.scopus.com/inward/record.url?scp=84924618437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924618437&partnerID=8YFLogxK

U2 - 10.1194/jlr.M055152

DO - 10.1194/jlr.M055152

M3 - Article

C2 - 25529920

AN - SCOPUS:84924618437

VL - 56

SP - 546

EP - 561

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 3

ER -