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