Degradation of cIAPs contributes to hepatocyte lipoapoptosis

Yuko Akazawa, Maria Eugenia Guicciardi, Sophie C. Cazanave, Steven F. Bronk, Nathan W. Werneburg, Keisuke Kakisaka, Kazuhiko Nakao, Gregory James Gores

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis. We have previously observed that the saturated free fatty acids (FFAs) induce hepatocyte apoptosis in part via a death receptor 5 (DR5)-mediated signaling pathway. Cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) proteins are potent inhibitors of death receptor-mediated apoptosis. However, the role of the cIAPs in FFA-mediated hepatocyte apoptosis is unexplored. Our aim was to determine whether cIAPs are dysregulated during hepatocyte lipoapoptosis. cIAP proteins underwent rapid cellular elimination following treatment with the saturated FFAs palmitate (PA) and stearate. In contrast, PA did not decrease cIAP-1 and cIAP-2 mRNA expression in the cells. Degradation of cIAPs was dependent on their E3-ligase activity, suggesting that cIAPs undergo autoubiquitination that leads to proteasomal degradation. Huh-7 cells stably expressing shRNA targeting cIAP-1, but not cIAP-2, displayed enhanced sensitivity to PA-mediated apoptosis. Incubation with the SMAC mimetic JP1584, which induces rapid degradation of cIAPs, also enhanced PA-mediated apoptosis. Hepatocytes isolated from DR5 knockout mice exhibited reduced apoptosis following treatment with PA plus JP1584, implying that degradation of cIAPs sensitizes to DR5-mediated cell death pathways. A decrease of cIAP-1 was also observed in tissue from patients with nonalcoholic steatohepatitis compared with normal obese subjects. Collectively, these results implicate proteasomal degradation of cIAPs by FFA as a mechanism contributing to hepatocyte lipoapoptosis.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume305
Issue number9
DOIs
StatePublished - Nov 1 2013

Fingerprint

Hepatocytes
Palmitates
Apoptosis
TNF-Related Apoptosis-Inducing Ligand Receptors
Nonesterified Fatty Acids
Inhibitor of Apoptosis Proteins
Fatty Acids
Stearates
Death Domain Receptors
Ubiquitin-Protein Ligases
Knockout Mice
Small Interfering RNA
Proteins
Cell Death
Messenger RNA
Therapeutics

Keywords

  • Apoptosis
  • DR5
  • Free fatty acids
  • IAPs
  • SMAC mimetics

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Degradation of cIAPs contributes to hepatocyte lipoapoptosis. / Akazawa, Yuko; Guicciardi, Maria Eugenia; Cazanave, Sophie C.; Bronk, Steven F.; Werneburg, Nathan W.; Kakisaka, Keisuke; Nakao, Kazuhiko; Gores, Gregory James.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 305, No. 9, 01.11.2013.

Research output: Contribution to journalArticle

Akazawa, Yuko ; Guicciardi, Maria Eugenia ; Cazanave, Sophie C. ; Bronk, Steven F. ; Werneburg, Nathan W. ; Kakisaka, Keisuke ; Nakao, Kazuhiko ; Gores, Gregory James. / Degradation of cIAPs contributes to hepatocyte lipoapoptosis. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2013 ; Vol. 305, No. 9.
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AU - Bronk, Steven F.

AU - Werneburg, Nathan W.

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AB - Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis. We have previously observed that the saturated free fatty acids (FFAs) induce hepatocyte apoptosis in part via a death receptor 5 (DR5)-mediated signaling pathway. Cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) proteins are potent inhibitors of death receptor-mediated apoptosis. However, the role of the cIAPs in FFA-mediated hepatocyte apoptosis is unexplored. Our aim was to determine whether cIAPs are dysregulated during hepatocyte lipoapoptosis. cIAP proteins underwent rapid cellular elimination following treatment with the saturated FFAs palmitate (PA) and stearate. In contrast, PA did not decrease cIAP-1 and cIAP-2 mRNA expression in the cells. Degradation of cIAPs was dependent on their E3-ligase activity, suggesting that cIAPs undergo autoubiquitination that leads to proteasomal degradation. Huh-7 cells stably expressing shRNA targeting cIAP-1, but not cIAP-2, displayed enhanced sensitivity to PA-mediated apoptosis. Incubation with the SMAC mimetic JP1584, which induces rapid degradation of cIAPs, also enhanced PA-mediated apoptosis. Hepatocytes isolated from DR5 knockout mice exhibited reduced apoptosis following treatment with PA plus JP1584, implying that degradation of cIAPs sensitizes to DR5-mediated cell death pathways. A decrease of cIAP-1 was also observed in tissue from patients with nonalcoholic steatohepatitis compared with normal obese subjects. Collectively, these results implicate proteasomal degradation of cIAPs by FFA as a mechanism contributing to hepatocyte lipoapoptosis.

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