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Research ArticleCellular and Molecular

Differential Roles of Unsaturated and Saturated Fatty Acids on Autophagy and Apoptosis in Hepatocytes

Shuang Mei, Hong-Min Ni, Sharon Manley, Abigail Bockus, Karen M. Kassel, James P. Luyendyk, Bryan L. Copple and Wen-Xing Ding
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 487-498; DOI: https://doi.org/10.1124/jpet.111.184341
Shuang Mei
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Hong-Min Ni
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Sharon Manley
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Abigail Bockus
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Karen M. Kassel
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James P. Luyendyk
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Bryan L. Copple
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Wen-Xing Ding
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Abstract

Fatty acid-induced lipotoxicity plays a critical role in the pathogenesis of nonalcoholic liver disease. Saturated fatty acids and unsaturated fatty acids have differential effects on cell death and steatosis, but the mechanisms responsible for these differences are not known. Using cultured HepG2 cells and primary mouse hepatocytes, we found that unsaturated and saturated fatty acids differentially regulate autophagy and apoptosis. The unsaturated fatty acid, oleic acid, promoted the formation of triglyceride-enriched lipid droplets and induced autophagy but had a minimal effect on apoptosis. In contrast, the saturated fatty acid, palmitic acid, was poorly converted into triglyceride-enriched lipid droplets, suppressed autophagy, and significantly induced apoptosis. Subsequent studies revealed that palmitic acid-induced apoptosis suppressed autophagy by inducing caspase-dependent Beclin 1 cleavage, indicating cross-talk between apoptosis and autophagy. Moreover, our data suggest that the formation of triglyceride-enriched lipid droplets and induction of autophagy are protective mechanisms against fatty acid-induced lipotoxicity. In line with our in vitro findings, we found that high-fat diet-induced hepatic steatosis was associated with autophagy in the mouse liver. Potential modulation of autophagy may be a novel approach that has therapeutic benefits for obesity-induced steatosis and liver injury.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant R21-AA017421]; the National Institutes of Health National Center for Research Resources [Grants P20-RR021940, P20-RR016475] (the first to W.-X.D. and J.P.L. and the second to W.-X.D); the National Institutes of Health National Institute of Environmental Health Sciences [Grant R01-ES017537] (to J.P.L.); and American Heart Association [Scientist Development Grant 0835121G] (to J.P.L.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.184341.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PA
    palmitic acid
    OA
    oleic acid
    TG
    triglyceride
    LC3
    light chain 3
    PE
    phosphatidylethanolamine
    CQ
    chloroquine
    BAF
    bafilomycin A1
    Beclin 1
    Bcl-2-interacting protein 1
    PI3K
    phosphatidylinositol 3-kinase
    p70S6K
    70-kDa ribosomal protein S6 kinase-1
    4EBP1
    translational initiation factor 4E binding protein-1
    BSA
    bovine serum albumin
    3-MA
    3-methyladenine
    NAC
    N-acetylcysteine
    TNF-α
    tumor necrosis factor-α
    Z-VAD-fmk
    N-benzyloxycarbonyl-Val-Ala-Asp(O-Met) fluoromethyl ketone
    TMRM
    tetramethylrhodamine methyl ester
    PBS
    phosphate-buffered saline
    GFP
    green fluorescent protein
    ANOVA
    analysis of variance
    EM
    electron microscopy
    AV
    autophagosomes
    LD
    lipid droplets
    ROS
    reactive oxygen species
    mTOR
    mammalian target of rapamycin
    ActD
    actinomycin D.

  • Received May 21, 2011.
  • Accepted August 18, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleCellular and Molecular

Fatty Acids Modulate Autophagy and Apoptosis

Shuang Mei, Hong-Min Ni, Sharon Manley, Abigail Bockus, Karen M. Kassel, James P. Luyendyk, Bryan L. Copple and Wen-Xing Ding
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 487-498; DOI: https://doi.org/10.1124/jpet.111.184341

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Research ArticleCellular and Molecular

Fatty Acids Modulate Autophagy and Apoptosis

Shuang Mei, Hong-Min Ni, Sharon Manley, Abigail Bockus, Karen M. Kassel, James P. Luyendyk, Bryan L. Copple and Wen-Xing Ding
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 487-498; DOI: https://doi.org/10.1124/jpet.111.184341
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