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      trans-Fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway

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          Abstract

          Food-borne trans-fatty acids (TFAs) are mainly produced as byproducts during food manufacture. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, including atherosclerosis. However, the underlying mechanisms in this disease etiology are largely unknown. Here we have shown that TFAs potentiate activation of apoptosis signal-regulating kinase 1 (ASK1) induced by extracellular ATP, a damage-associated molecular pattern leaked from injured cells. Major food-associated TFAs such as elaidic acid (EA), linoelaidic acid, and trans-vaccenic acid, but not their corresponding cis isomers, dramatically enhanced extracellular ATP-induced apoptosis, accompanied by elevated activation of the ASK1-p38 pathway in a macrophage-like cell line, RAW264.7. Moreover, knocking out the ASK1-encoding gene abolished EA-mediated enhancement of apoptosis. We have reported previously that extracellular ATP induces apoptosis through the ASK1-p38 pathway activated by reactive oxygen species generated downstream of the P2X purinoceptor 7 (P2X 7). However, here we show that EA did not increase ATP-induced reactive oxygen species generation but, rather, augmented the effects of calcium/calmodulin-dependent kinase II-dependent ASK1 activation. These results demonstrate that TFAs promote extracellular ATP-induced apoptosis by targeting ASK1 and indicate novel TFA-associated pathways leading to inflammatory signal transduction and cell death that underlie the pathogenesis and progression of TFA-induced atherosclerosis. Our study thus provides insight into the pathogenic mechanisms of and proposes potential therapeutic targets for these TFA-related disorders.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
          0021-9258
          1083-351X
          19 May 2017
          29 March 2017
          : 292
          : 20
          : 8174-8185
          Affiliations
          From the []Laboratory of Health Chemistry,
          [§ ]Laboratory of Molecular and Cellular Biochemistry, and
          []Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, 980-8578 Sendai, Japan and
          the []Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology, Chiyoda-ku, 100-0004 Tokyo, Japan
          Author notes
          [2 ] To whom correspondence may be addressed. Tel.: 81-22-795-6828; Fax: 81-22-795-6826; E-mail: noguchi@ 123456m.tohoku.ac.jp .
          [3 ] To whom correspondence may be addressed. Tel.: 81-22-795-6827; Fax: 81-22-795-6826; E-mail: matsushi@ 123456m.tohoku.ac.jp .
          [1]

          These authors contributed equally to this work.

          Edited by George M. Carman

          Article
          PMC5437226 PMC5437226 5437226 M116.771519
          10.1074/jbc.M116.771519
          5437226
          28360100
          90046186-0393-466e-aa53-459be798397d
          © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
          History
          : 7 December 2016
          : 29 March 2017
          Funding
          Funded by: Japan Society for the Promotion of Science , open-funder-registry 10.13039/501100001691;
          Funded by: Ministry of Education, Culture, Sports, Science, and Technology , open-funder-registry 10.13039/501100001700;
          Funded by: Pharmaceutical Society of Japan Nagai Memorial Research Scholarship
          Categories
          Cell Biology

          macrophage,p38 MAPK,P2X7,apoptosis signal-regulating kinase 1 (ASK1),apoptosis

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