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

135 Citations (Scopus)

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 1 2010

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Palmitates
Hepatocytes
Up-Regulation
Endoplasmic Reticulum Stress
Nonesterified Fatty Acids
Stearates
Cell Line
Proteins
Cytoprotection
palmitoleic acid
Unsaturated Fatty Acids
Fatty Acids
Phosphorylation
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. / Akazawa, Yuko; Cazanave, Sophie; Mott, Justin L; Elmi, Nafisa; Bronk, Steven F.; Kohno, Shigeru; Charlton, Michael R.; Gores, Gregory J.

In: Journal of Hepatology, Vol. 52, No. 4, 01.04.2010, p. 586-593.

Research output: Contribution to journalArticle

Akazawa, Y, Cazanave, S, Mott, JL, Elmi, N, Bronk, SF, Kohno, S, Charlton, MR & Gores, GJ 2010, 'Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis', Journal of Hepatology, vol. 52, no. 4, pp. 586-593. https://doi.org/10.1016/j.jhep.2010.01.003
Akazawa, Yuko ; Cazanave, Sophie ; Mott, Justin L ; Elmi, Nafisa ; Bronk, Steven F. ; Kohno, Shigeru ; Charlton, Michael R. ; Gores, Gregory J. / Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. In: Journal of Hepatology. 2010 ; Vol. 52, No. 4. pp. 586-593.
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T1 - Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis

AU - Akazawa, Yuko

AU - Cazanave, Sophie

AU - Mott, Justin L

AU - Elmi, Nafisa

AU - Bronk, Steven F.

AU - Kohno, Shigeru

AU - Charlton, Michael R.

AU - Gores, Gregory J.

PY - 2010/4/1

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N2 - 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.

AB - 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.

KW - Apoptosis

KW - Bcl-2 proteins

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KW - Human hepatocytes

KW - Nile Red

KW - Steatosis

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