Abstract
trans-Fatty acids (TFAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)-interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / radiation effects
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Caenorhabditis elegans
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Cell Line, Tumor
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DNA Fragmentation / drug effects*
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DNA Fragmentation / radiation effects
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Doxorubicin / pharmacology
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Embryo, Nonmammalian
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Feedback, Physiological
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Gene Expression Regulation
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Guanine Nucleotide Exchange Factors / antagonists & inhibitors
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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HEK293 Cells
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HeLa Cells
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Linoleic Acid / pharmacology*
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Mice
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Oleic Acids / pharmacology*
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Osteoblasts / cytology
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Osteoblasts / drug effects
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Osteoblasts / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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RAW 264.7 Cells
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / agonists
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Reactive Oxygen Species / metabolism*
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Ultraviolet Rays
Substances
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Adaptor Proteins, Signal Transducing
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Caenorhabditis elegans Proteins
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Guanine Nucleotide Exchange Factors
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Oleic Acids
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REI-1 protein, C elegans
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RNA, Small Interfering
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Reactive Oxygen Species
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SH3BP5 protein, human
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elaidic acid
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Doxorubicin
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Linoleic Acid
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JNK Mitogen-Activated Protein Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 6