CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis

Sophie C. Cazanave, Nafisa A. Elmi, Yuko Akazawa, Steven F. Bronk, Justin L. Mott, Gregory J. Gores

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress-mediated apoptosis is a key feature of hepatocyte cytotoxicity by saturated free fatty acids (FFA). This lipoapoptosis is dependent, in part, on the transcriptional upregulation of the BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Although the activator protein (AP)-1 complex facilitates PUMA expression by saturated FFA, the transcription factor CAAT/enhancer binding homologous protein (CHOP) is also induced by ER stress and promotes apoptosis. To integrate the role of these two transcription factors in ER stress-induced apoptosis, we examined the relative contribution of CHOP and AP-1 in mediating PUMA induction by saturated FFA. Our results demonstrate that short-hairpin RNA-targeted knockdown of CHOP attenuates palmitate-induced apoptosis in Huh-7 cells. Loss of CHOP induction also reduced the increase in PUMA mRNA and protein levels as well as Bax activation by palmitate. No functional CHOP binding sites were identified in the PUMA promoter sequence. Rather, we observed that CHOP physically interacts with the AP-1 complex protein c-Jun upon palmitate treatment, and a CHOP:phosphorylated c-Jun heteromeric complex binds to the AP-1 consensus binding sequence within the PUMA promoter region. Finally, loss of function studies suggest that both transcription factors are necessary for maximal PUMA induction. Collectively, these data suggest that CHOP and AP-1 cooperatively mediate PUMA induction during hepatocyte lipoapoptosis.

Original languageEnglish (US)
Pages (from-to)G236-G243
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume299
Issue number1
DOIs
StatePublished - Jul 1 2010

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CCAAT-Enhancer-Binding Proteins
Transcription Factor AP-1
Apoptosis
Endoplasmic Reticulum Stress
Palmitates
Nonesterified Fatty Acids
Transcription Factors
Fatty Acids
Hepatocytes
Proto-Oncogene Proteins c-jun
Consensus Sequence
Genetic Promoter Regions
Protein Binding
Small Interfering RNA

Keywords

  • Activator protein-1
  • BH3-only proteins
  • CAAT/enhancer binding homologous protein
  • Endoplasmic reticulum stress
  • Hepatic steatosis
  • Nonalcoholic steatohepatitis
  • c-Jun
  • p53 upregulated modulator of apoptosis

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. / Cazanave, Sophie C.; Elmi, Nafisa A.; Akazawa, Yuko; Bronk, Steven F.; Mott, Justin L.; Gores, Gregory J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 299, No. 1, 01.07.2010, p. G236-G243.

Research output: Contribution to journalArticle

Cazanave, Sophie C. ; Elmi, Nafisa A. ; Akazawa, Yuko ; Bronk, Steven F. ; Mott, Justin L. ; Gores, Gregory J. / CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2010 ; Vol. 299, No. 1. pp. G236-G243.
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