Double Bond In Trans Configuration Research Articles

A comprehensive toxicological analysis of trans-fatty acids (TFAs) reveals a pro-apoptotic action specific to industrial TFAs counteracted by polyunsaturated FAs

trans-Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon–carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.

Molecular Mechanisms Underlying Toxic Actions of trans-Fatty Acids and Prevention of Related Diseases

trans-Fatty acids (TFAs), including elaidic acid and linoelaidic acid, are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. TFAs are not synthesized in the human body, but are taken into the body from various foods, which are mainly produced during industrial food manufacturing. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, such as atherosclerosis, cardiovascular diseases, allergic diseases, and dementia. However, the underlying pathogenic mechanisms of TFA-related disorders and the specific molecular targets evoking TFA toxicity are largely unknown. To elucidate the molecular mechanisms by which TFAs cause the cytotoxicity, we focused on cell death and inflammation, which are the main and common pathogenesis of the TFA-related diseases, and analyzed the effects of TFAs on cellular responses to various stimulations inducing cell death and inflammation. This review provides recent progress in our studies on the molecular mechanisms causing toxic actions of TFAs, which lead to diverse TFA-related disorders.

Elaidic Acid Potentiates Extracellular ATP-Induced Apoptosis via the P2X7-ROS-ASK1-p38 Axis in Microglial Cell Lines.

trans-Fatty acids (TFAs) are unsaturated fatty acids with at least one carbon-carbon double bond in trans configuration. TFA consumption has been epidemiologically associated with neurodegenerative diseases (NDs) including Alzheimer's disease. However, the underlying mechanisms of TFA-related NDs remain unknown. Here, we show a novel microglial signaling pathway that induces inflammation and cell death, which is dramatically enhanced by elaidic acid (EA), the most abundant TFA derived from food. We found that extracellular ATP, one of the damage-associated molecular patterns (DAMPs) leaked from injured cells, induced activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway, which is one of the major stress-responsive mitogen-activated protein (MAP) kinase signaling pathways, and subsequent caspase-3 cleavage and DNA ladder formation (hallmarks of apoptosis) in mouse microglial cell lines including BV2 and MG6 cells. Furthermore, we found that in these microglial cell lines, EA, but not its cis isomer oleic acid, facilitated extracellular ATP-induced ASK1/p38 activation and apoptosis, which was suppressed by pharmacological inhibition of either p38, reactive oxygen species (ROS) generation, P2X purinoceptor 7 (P2X7), or Ca2+/calmodulin-dependent kinase II (CaMKII). These results demonstrate that in microglial cells, extracellular ATP induces activation of the ASK1-p38 MAP kinase pathway and ultimately apoptosis downstream of P2X7 receptor and ROS generation, and that EA promotes ATP-induced apoptosis through CaMKII-dependent hyperactivation of the ASK1-p38 pathway, in the same manner as in macrophages. Our study may provide an insight into the pathogenesis of NDs associated with TFAs.

Regulatory Changes Affecting the Production and Use of Fats and Oils: Focus on Partially Hydrogenated Oils

AbstractPartially hydrogenated oils (PHO), the products of incomplete catalytic hydrogenation of food oils, have been widely employed by the food industry for more than a century. Their exceptional stability and technologic characteristics made them the preferred choice for the production of several food products including margarines, bakery goods, and frying oils. Some of these highly prized characteristics were provided by the high content in trans fatty acids (TFA), defined as fatty acids with one or more isolated double bond in trans configuration. The discovery of negative health effects associated with dietary intake of TFA triggered world‐wide a wave of regulatory actions aimed to curb their consumption. PHO became the main target of most campaigns aimed to reduce consumption of TFA, and their fortune in the food industry progressively faded. At the 2017, AOCS Annual Meeting in Orlando, a group of experts from regulatory agencies and industry from North America and Europe met to discuss the current status of government regulations and industry adaptations regarding the productions and use of PHO. The discussion was enriched by including the impact on fats and oils production of the 2016 amendment of the Toxic Substances Control Act of 1976 (TSCA). The present publication may not include all regulatory changes that took place after this symposium, in 2017.

Trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop

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.

Evaluation of the Impact of Ruminant Trans Fatty Acids on Human Health: Important Aspects to Consider

The definition and evaluation of trans fatty acids (TFA) with regard to foodstuffs and health hazard are not consistent. Based on the current situation, the term should be restricted only to TFA with isolated double bonds in trans-configuration. Conjugated linoleic acids (CLA) should be separately assessed. Ideally, the origin of the consumed fat should be declared, i.e., ruminant TFA (R-TFA) and industrial TFA (non-ruminant; I-TFA). In ruminant fat, more than 50% of R-TFA consists of vaccenic acid (C18:1 t11). In addition, natural CLA, i.e., c9,t11 CLA is also present. Both are elevated in products from organic farming. In contrast to elaidic acid (t9) and t10, which occur mainly in partially hydrogenated industrial fat, t11 is partially metabolized into c9,t11 CLA via Δ9-desaturation. This is the major metabolic criterion used to differentiate between t11 and other trans C18:1. t11 indicates health beneficial effects in several studies. Moreover, CLA in milk fat is associated with the prevention of allergy and asthma. An analysis of the few studies relating to R-TFA alone makes clear that no convincing adverse physiological effect can be attributed to R-TFA. Only extremely high R-TFA intakes cause negative change in blood lipids. In conclusion, in most European countries, the intake of R-TFA is assessed as being low to moderate. Restriction of R-TFA would unjustifiably represent a disadvantage for organic farming of milk.

MiRNA expression in human intestinal Caco-2 cells is comparably regulated by cis- and trans-fatty acids.

Trans-fatty acids are unsaturated fatty acids with at least one double bond in trans configuration. While their role in the development of coronary heart disease is broadly accepted, a potential impact of these fatty acids on colon carcinogenesis is still under discussion. MiRNAs are small non-coding RNAs that regulate the gene expression at a post-transcriptional level by inhibiting the translation of target mRNAs. We investigated the effect of 16 different C 18 fatty acid isomers on the expression of 84 cancer-related miRNAs in the human colorectal adenocarcinoma cell line Caco-2 by using a qRT-PCR array. 66 of these 84 miRNAs were deregulated by at least one fatty acid, however, there was no trans-specific impact on miRNA expression as the corresponding cis isomer of a given fatty acid generally had comparable effects on the miRNA expression profile. The most pronounced effects were observed for hsa-miR-146a-5p, which was upregulated by four of the 16 investigated fatty acids, and hsa-miR-32-5p, which was strongly downregulated by five fatty acids. As hsa-miR-32-5p was described to target genes being involved in the regulation of apoptosis, the effect of α-eleostearic acid on the expression of the apoptosis-associated genes BCL2L11, BCL-2, and BCL-XL was examined. The qPCR results indicate that fatty acid-mediated downregulation of hsa-miR-32-5p is accompanied by a downregulation of BCL-2 and BCL2L11 mRNA whereas BCL-XL was shown to be simultaneously upregulated. In conclusion, our data indicate that several fatty acids are able to regulate miRNA expression of human colon cancer cells. However, no trans-specific regulation was observed.

1-(p-Fluorophenyl)-2-(2′-pyridyl)ethanol and 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene obtained from the condensation reaction of 2-picoline and p-fluorophenylaldehyde under catalyst-and solvent-free conditions

The novel intermediate 1-(p-fluorophenyl)-2-(2′-pyridyl)ethanol or 2-[2′-(1-hydroxy-1-(p-fluorophenyl)ethyl]pyridine and the corresponding novel dehydration compound 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene or 2-[p-fluorophenylvinyl]pyridine were obtained from the condensation reaction of p-fluorophenylaldehyde and 2-picoline under catalyst-and solvent-free conditions. The intermediate 1-(p-fluorophenyl)-2-(2′-pyridyl)ethanol was obtained at 42 h reaction time and temperature of 120°C, respectively. 1H-NMR, IR spectroscopic data of the 1-(p-fluorophenyl)-2-(2-pyridyl)ethanol clearly showed the presence of the-CH2-CHOH-group. The compound was obtained as a white powder with m.p. 121–122°C and a yield of 8%. For 1-(p-fluorophenyl)-2-(2-pyridyl)ethene, the reaction conditions were similar, but the reaction temperature was increased to yield the double bond in the 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene. At the reaction temperature of 140°C, the compound was a slightly brown powder with a m.p. of 78°C and yield of 18%. 1H-NMR, IR spectroscopic data for the 1-(p-fluorophenyl)-2-(2′-pyridyl)ethene showed the presence of a double bond in trans configuration (-CH=CH-), characteristic of a styrylpyridine.

Efficient epoxidation of unsaturated fatty acids by a hydroperoxide-dependent oxygenase.

Detergent-solubilized and partially purified soybean peroxygenase was shown to actively catalyze, in the presence of alkylhydroperoxides as co-substrates, the epoxidation of mono- and polyunsaturated fatty acids such as oleic and linoleic acids. Octadecenoic acids were found to be better substrates than shorter mono-unsaturated fatty acids (C16:1 or C14:1), but the position of their double bond (at positions 6, 9, or 11) had little effect on the rates of epoxidation. The peroxygenase exhibits a strong stereospecificity since octadecenoic acids with double bonds in trans-configuration were not epoxidized at detectable rates. Oxidation of linoleic acid yielded the two positional monoepoxide isomers and, as the minor product, the diepoxide. An important regioselectivity was, however, observed in this case; i.e. the unsaturation at position 9,10 was epoxidized preferentially to that at 12, 13. Oxidation of oleic acid in the presence of 18O-labeled hydroperoxy-linoleic acid revealed an incorporation of about 80% of the label into the epoxide ring. Products similar to those formed by the peroxygenase by epoxidation of unsaturated free fatty acids such as linoleic acid have been described as important metabolites (leukotoxins) in the defense of plants, e.g. in fungal agressions. This aspect underlines the physiological relevance of this new and potent catalytic activity of the peroxygenase.

Deuterium‐hydrogen exchange during the catalytic deuteration of methyl oleate

AbstractExtensive exchange of deuterium for carbonbonded hydrogen takes place during the catalytic reduction of methyl oleate with gaseous deuterium. Mass spectrometric analysis of the deuterated stearate shows that it is composed as follows: a small part of one molecular species contains no deuterium; the largest contains 1 atom of deuterium; nearly as much contains 2 atoms; and progressively smaller numbers of molecules contain 3,4,5, and up to 11 atoms of deuterium per molecule.No appreciable exchange occurred with the hydrogen of methyl stearate in the presence of active palladium catalyst and deuterium.Methyl oleate, containing up to 9 atoms of deuterium in one species and 11/2 moles of deuterium average per mole, has been separated from the partially deuterated ester. This octadecenoate has 60舑65% of its double bonds intrans configuration and only 18% of its double bonds in the original 9,10‐position.