Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis

Yuko Akazawa, Sophie Cazanave, Justin L. Mott, Nafisa Elmi, Steven F. Bronk, Shigeru Kohno, Michael R. Charlton, Gregory J. Gores

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

Background & Aims: Saturated free fatty acids induce hepatocyte lipoapoptosis. This lipotoxicity involves an endoplasmic reticulum stress response, activation of JNK, and altered expression and function of Bcl-2 proteins. The mono-unsaturated free fatty acid palmitoleate is an adipose-derived lipokine which suppresses free fatty acid-mediated lipotoxicity by unclear mechanisms. Herein we examined the mechanisms responsible for cytoprotection. Methods: We employed isolated human and mouse primary hepatocytes, and the Huh-7 and Hep 3B cell lines for these studies. Cells were incubated in presence and absence of palmitate (16:0), stearate (18:0), and or palmitoleate (16:1, n-7). Results: Palmitoleate significantly reduced lipoapoptosis by palmitate or stearate in both primary cells and cell lines. Palmitoleate accentuated palmitate-induced steatosis in Huh-7 cells excluding inhibition of steatosis as a mechanism for reduced apoptosis. Palmitoleate inhibited palmitate induction of the endoplasmic reticulum stress response as demonstrated by reductions in CHOP expression, eIF2-α phosphorylation, XBP-1 splicing, and JNK activation. Palmitate increased expression of the BH3-only proteins PUMA and Bim, which was attenuated by palmitoleate. Consistent with its inhibition of PUMA and Bim induction, palmitoleate prevented activation of the downstream death mediator Bax. Conclusions: These data suggest palmitoleate inhibits lipoapoptosis by blocking endoplasmic reticulum stress-associated increases of the BH3-only proteins Bim and PUMA.

Original languageEnglish (US)
Pages (from-to)586-593
Number of pages8
JournalJournal of Hepatology
Volume52
Issue number4
DOIs
StatePublished - Apr 2010

Keywords

  • Apoptosis
  • Bcl-2 proteins
  • Endoplasmic reticulum stress
  • Human hepatocytes
  • Nile Red
  • Steatosis

ASJC Scopus subject areas

  • Hepatology

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    Akazawa, Y., Cazanave, S., Mott, J. L., Elmi, N., Bronk, S. F., Kohno, S., Charlton, M. R., & Gores, G. J. (2010). Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. Journal of Hepatology, 52(4), 586-593. https://doi.org/10.1016/j.jhep.2010.01.003