Journal
JOURNAL OF HEPATOLOGY
Volume 52, Issue 4, Pages 586-593Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2010.01.003
Keywords
Apoptosis; Bcl-2 proteins; Endoplasmic reticulum stress; Human hepatocytes; Nile Red; Steatosis
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Funding
- NIH [OK 41876, DK 79875, DK 69757]
- Optical Microscopy Core [P30 DK 84567]
- Mayo Foundation
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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.
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