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

JOURNAL OF HEPATOLOGY

卷:52

Article

Akazawa, Yuko^1,2  Cazanave, Sophie¹  Mott, Justin L.¹  Elmi, Nafisa¹  Bronk, Steven F.¹  Kohno, Shigeru²  Charlton, Michael R.¹  Gores, Gregory J.¹ 

[1] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[2] Nagasaki Univ, Sch Med, Dept Internal Med 2, Nagasaki 8528562, Japan

关键词: Apoptosis;    Bcl-2 proteins;    Endoplasmic reticulum stress;    Human hepatocytes;    Nile Red;    Steatosis;   

DOI  :  10.1016/j.jhep.2010.01.003

来源: Elsevier

【 摘 要 】

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, elF2-alpha 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. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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