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

Abstract

Food-borne -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 -vaccenic acid, but not their corresponding 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). 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.

Elevated Serum Elaidic Acid Predicts Risk of Repeat Revascularization After Percutaneous Coronary Intervention in Japan

“…30 In contrast, TFA promote pro-inflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1/p38 pathway. 31 In the present study, we demonstrated the relationship between circulating elaidic acid level and the incidence of TLR. Elaidic acid is a typical industrial TFA, produced by partial hydrogenation of vegetable oil.…”

The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells

“…Cells were lysed with the 1% Triton X-100 buffer [20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% Triton-X100, 10% Glycerol, and 1% protease inhibitor cocktails (Nacalai Tesque, Kyoto, Japan)]. After centrifugation, the cell extracts were resolved by SDS-PAGE and analyzed as described previously (Hirata et al, 2017). The blots were developed with ECL (Merck Millipore, Burlington, VT, USA).…”

“…Guide RNAs (gRNAs) were designed to target a region in the exon 3 of p53 gene (5'-ATCTGAGCAGCGCTCATGGTGGG-3'), and the exon 4 of EGFR gene (5'-CTTTCTCAGCAA-CATGTCGATGG-3') using CRISPRdirect. gRNA-encoding oligonucleotide was cloned into lentiCRISPRv2 plasmid (addgene, Watertown, NY, USA), and knockout cells were established as previously described (Hirata et al, 2017). To determine the mutations of p53 and EGFR in cloned cells, genomic sequence around the target region was analyzed by PCR-direct sequencing using extracted DNA from each clone as a template and the following primers: 5'-AGAGACCCCAGTTGCAAACC-3'and 5'-CCCTGCCCTCAACAAGATGT-3' for p53, and primers: 5'-GGGCTAATTGCGGGACTCTT-3' and 5'-CCCAGTGCTGTAGAGCTGTC-3' for EGFR.…”

Mechanisms of isomerization and oxidation in heated trilinolein by DFT method

“…3,4 Trans fatty acids affect the activities of macrophages, leading to an increase in pro-inammatory reactions and the occurrence of atherosclerosis. [5][6][7] Trans fatty acids can decrease the level of high-density lipoprotein cholesterol (HDL) and increase the level of low-density lipoprotein cholesterol (LDL), thereby increasing the risk of coronary heart disease. [8][9][10] It is well known that primary oxidation compounds or hydroperoxides can be formed in the oxidation of edible oils at high temperature or in the presence of metals, which can then be degraded to secondary oxidation compounds.…”