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.
Highlights
Trans-Fatty acids (TFAs) are defined as unsaturated fatty acids containing one or more carbon-carbon double bonds in trans configuration
We previously showed that elaidic acid (EA) promotes extracellular ATP-induced cell death, which was not suppressed by co-treatment of OA11
We unexpectedly found that p53 deficiency significantly promoted Dox-induced cell death, but we still observed that EA promoted cell death in p53 KO cells to the similar level as that in wild type (WT) cells (Fig. 2f), suggesting that p53-dependent mitochondrial apoptosis is not involved in the enhancement of cell death by EA
Summary
Trans-Fatty acids (TFAs) are defined as unsaturated fatty acids containing one or more carbon-carbon double bonds in trans configuration. Major food-associated TFAs, including EA, but not their corresponding cis isomers, promote extracellular ATP-induced apoptosis in a macrophage cell line RAW264.7, through enhancing activation of the apoptosis www.nature.com/scientificreports signal-regulating kinase 1 (ASK1)-p38 mitogen activated protein (MAP) kinase pathway downstream of the P2X purinoceptor 7 (P2X7)[11]. These findings provided a novel mechanistic insight into TFA-related atherosclerosis, where macrophage apoptosis in atherosclerotic lesions is the major cause of disease progression[12,13]. These results demonstrate a TFA-specific pro-apoptotic effect on diverse cell types during DNA damage, which explains the common pathogenesis and progression of various TFA-related disorders
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