Death receptor 5 signaling promotes hepatocyte lipoapoptosis

Sophie C. Cazanave, Justin L. Mott, Steven F. Bronk, Nathan W. Werneburg, Christian D. Fingas, X. Wei Meng, Niklas Finnberg, Wafik S. El-Deiry, Scott H Kaufmann, Gregory James Gores

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR -/-) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligandindependent cytotoxic signaling by this death receptor.

Original languageEnglish (US)
Pages (from-to)39336-39348
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number45
DOIs
StatePublished - Nov 11 2011

Fingerprint

TNF-Related Apoptosis-Inducing Ligand Receptors
Hepatocytes
Palmitates
Endoplasmic Reticulum Stress
Caspase 8
Nonesterified Fatty Acids
Chemical activation
Initiator Caspases
Up-Regulation
Apoptosis
Ligands
Death Domain Receptors
Poisons
Cell Surface Receptors
Cell death
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cazanave, S. C., Mott, J. L., Bronk, S. F., Werneburg, N. W., Fingas, C. D., Meng, X. W., ... Gores, G. J. (2011). Death receptor 5 signaling promotes hepatocyte lipoapoptosis. Journal of Biological Chemistry, 286(45), 39336-39348. https://doi.org/10.1074/jbc.M111.280420

Death receptor 5 signaling promotes hepatocyte lipoapoptosis. / Cazanave, Sophie C.; Mott, Justin L.; Bronk, Steven F.; Werneburg, Nathan W.; Fingas, Christian D.; Meng, X. Wei; Finnberg, Niklas; El-Deiry, Wafik S.; Kaufmann, Scott H; Gores, Gregory James.

In: Journal of Biological Chemistry, Vol. 286, No. 45, 11.11.2011, p. 39336-39348.

Research output: Contribution to journalArticle

Cazanave, SC, Mott, JL, Bronk, SF, Werneburg, NW, Fingas, CD, Meng, XW, Finnberg, N, El-Deiry, WS, Kaufmann, SH & Gores, GJ 2011, 'Death receptor 5 signaling promotes hepatocyte lipoapoptosis', Journal of Biological Chemistry, vol. 286, no. 45, pp. 39336-39348. https://doi.org/10.1074/jbc.M111.280420
Cazanave SC, Mott JL, Bronk SF, Werneburg NW, Fingas CD, Meng XW et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis. Journal of Biological Chemistry. 2011 Nov 11;286(45):39336-39348. https://doi.org/10.1074/jbc.M111.280420
Cazanave, Sophie C. ; Mott, Justin L. ; Bronk, Steven F. ; Werneburg, Nathan W. ; Fingas, Christian D. ; Meng, X. Wei ; Finnberg, Niklas ; El-Deiry, Wafik S. ; Kaufmann, Scott H ; Gores, Gregory James. / Death receptor 5 signaling promotes hepatocyte lipoapoptosis. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 45. pp. 39336-39348.
@article{bec8294170c64bb7891e307eb1880cdc,
title = "Death receptor 5 signaling promotes hepatocyte lipoapoptosis",
abstract = "Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR -/-) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligandindependent cytotoxic signaling by this death receptor.",
author = "Cazanave, {Sophie C.} and Mott, {Justin L.} and Bronk, {Steven F.} and Werneburg, {Nathan W.} and Fingas, {Christian D.} and Meng, {X. Wei} and Niklas Finnberg and El-Deiry, {Wafik S.} and Kaufmann, {Scott H} and Gores, {Gregory James}",
year = "2011",
month = "11",
day = "11",
doi = "10.1074/jbc.M111.280420",
language = "English (US)",
volume = "286",
pages = "39336--39348",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "45",

}

TY - JOUR

T1 - Death receptor 5 signaling promotes hepatocyte lipoapoptosis

AU - Cazanave, Sophie C.

AU - Mott, Justin L.

AU - Bronk, Steven F.

AU - Werneburg, Nathan W.

AU - Fingas, Christian D.

AU - Meng, X. Wei

AU - Finnberg, Niklas

AU - El-Deiry, Wafik S.

AU - Kaufmann, Scott H

AU - Gores, Gregory James

PY - 2011/11/11

Y1 - 2011/11/11

N2 - Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR -/-) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligandindependent cytotoxic signaling by this death receptor.

AB - Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR -/-) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligandindependent cytotoxic signaling by this death receptor.

UR - http://www.scopus.com/inward/record.url?scp=80655149472&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80655149472&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.280420

DO - 10.1074/jbc.M111.280420

M3 - Article

C2 - 21941003

AN - SCOPUS:80655149472

VL - 286

SP - 39336

EP - 39348

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -