Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis.
Journal of hepatology
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-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.
Animals, Apoptosis, Apoptosis Regulatory Proteins, Cell Line, Tumor, DNA-Binding Proteins, Drug Interactions, Endoplasmic Reticulum, Fatty Acids, Monounsaturated, Fatty Liver, Hepatocytes, Humans, JNK Mitogen-Activated Protein Kinases, Membrane Proteins, Mice, Palmitates, Phosphorylation, Proto-Oncogene Proteins, RNA, Messenger, Stress, Physiological, Transcription Factor CHOP, Transcription Factors, Tumor Suppressor Proteins, Up-Regulation, bcl-2-Associated X Protein
Akazawa, Yuko; Cazanave, Sophie; Mott, Justin L.; Elmi, Nafisa; Bronk, Steven F.; Kohno, Shigeru; Charlton, Michael R.; and Gores, Gregory J., "Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis." (2010). Journal Articles: Biochemistry & Molecular Biology. 14.
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NOTICE: this is the author’s version of a work that was accepted for publication in Journal of hepatology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of hepatology, [52, 4, (2010)] DOI#10.1016/j.jhep.2010.01.003.