Oxylipin

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The structural formulae of selected oxylipins Oxylipins.jpg
The structural formulae of selected oxylipins

Oxylipins constitute a family of oxygenated natural products which are formed from fatty acids by pathways involving at least one step of dioxygen-dependent oxidation. [1] These small polar lipid compounds are metabolites of polyunsaturated fatty acids (PUFAs) including omega-3 fatty acids and omega-6 fatty acids. [2] [3] Oxylipins are formed by enyzmatic or non-enzymatic oxidation of PUFAs. [2]

Contents

In animal species, four main pathways of oxylipin production prevail: lipoxygenases (LOXs) pathway, cyklooxygenases (COXs) route, cytochrome P450 (CYPs) pathway, and reactive oxygen species (ROS) route. [4] These pathways result in formation of many different oxylipin molecules which are important for number of processes in living organisms. The processes include inflamation, blood flow, energy metabolism, cellular life, cell signaling, or muscle contractions. [2] [3] [4] Oxylipins have both pro- and anti-inflamatory roles. [5]

Oxylipins are widespread in aerobic organisms including plants, animals and fungi. Many of oxylipins have physiological significance. [6] [7] Typically, oxylipins are not stored in tissues but are formed on demand by liberation of precursor fatty acids from esterified forms.

Biosynthesis

Biosynthesis of oxylipins is initiated by dioxygenases or monooxygenases; however also non-enzymatic autoxidative processes contribute to oxylipin formation (phytoprostanes, isoprostanes). Dioxygenases include lipoxygenases (plants, animals, fungi), heme-dependent fatty acid oxygenases (plants, fungi), and cyclooxygenases (animals). Fatty acid hydroperoxides or endoperoxides are formed by action of these enzymes. Monooxygenases involved in oxylipin biosynthesis are members of the cytochrome P450 superfamily and can oxidize double bonds with epoxide formation or saturated carbons forming alcohols. Nature has evolved numerous enzymes which metabolize oxylipins into secondary products, many of which possess strong biological activity. Of special importance are the cytochrome P450 enzymes in animals, including CYP5A1 (thromboxane synthase), CYP8A1 (prostacyclin synthase), and the CYP74 family of hydroperoxide-metabolizing enzymes in plants, lower animals and bacteria. In the plant and animal kingdoms the C18 and C20 polyenoic fatty acids, respectively, are the major precursors of oxylipins.

Structure and function

Oxylipins in animals, referred to as eicosanoids (Greek icosa; twenty) because of their formation from twenty-carbon essential fatty acids, have potent and often opposing effects on e.g. smooth muscle (vasculature, myometrium) and blood platelets. Certain eicosanoids (leukotrienes B4 and C4) are proinflammatory whereas others (resolvins, protectins) are antiinflammatory and are involved in the resolution process which follows tissue injury. Plant oxylipins are mainly involved in control of ontogenesis, reproductive processes and in the resistance to various microbial pathogens and other pests.

Oxylipins most often act in an autocrine or paracrine manner, notably in targeting peroxisome proliferator-activated receptors (PPARs) to modify adipocyte formation and function. [8]

Most oxylipins in the body are derived from linoleic acid or alpha-linolenic acid. Linoleic acid oxylipins are usually present in blood and tissue in higher concentrations than any other PUFA oxylipin, despite the fact that alpha-linolenic acid is more readily metabolized to oxylipin. [9]

Linoleic acid oxylipins can be anti-inflammatory, but are more often pro-inflammatory, associated with atherosclerosis, non-alcoholic fatty liver disease, and Alzheimer's disease. [9] Centenarians have shown reduced levels of linoleic acid oxylipins in their blood circulation. [10] Lowering dietary linoleic acid results in fewer linoleic acid oxylipins in humans. [11] From 1955 to 2005 the linoleic acid content of human adipose tissue has risen an estimated 136% in the United States. [12]

In general, oxylipins derived from omega-6 fatty acids are more pro-inflammatory, vasoconstrictive, and proliferative than those derived from omega-3 fatty acids. [9] The omega-3 eicosapentaenoic acid (EPA)-derived and docosahexaenoic acid (DHA)-derived oxylipins are anti-inflammatory and vasodilatory. [9] In a clinical trial of men with high triglycerides, 3 grams daily of DHA compared with placebo (olive oil) given for 91 days nearly tripled the DHA in red blood cells while reducing oxylipins in those cells. [13] Both groups were given Vitamin C (ascorbyl palmitate) and Vitamin E (mixed tocopherol) supplements. [13]

Oxylipins and disease

Oxylipins play important role in many diseases, for example, diabetes, obesity, cardiovascular diseases, cancer, COVID-19, or neurodegenerative disorders. Changes in oxylipin metabolism have been reported in these diseases. [3] [4] [14] [15] [16] [17] In 2021, Alzheimer's disease was associated with changes in oxylipin levels in plasma and cerebrospinal fluid (CSF) for the first time. [18] Interestingly, improvement in neurodegenerative diseases and also cardiovascular diseases may be achieved by using inhibitors of an enzyme (soluble epoxide hydrolase) involved in formation of oxylipins. [19] [20] In Parkinson's disease, oxylipin profiles reflect the stage of the disease. This should be taken into consideration when choosing the suitable medication for Parkinson's disease. [15]

Related Research Articles

Essential fatty acids, or EFAs, are fatty acids that are required by humans and other animals for normal physiological function that cannot be synthesized in the body.⁠ As they are not synthesized in the body, the essential fatty acids – alpha-linolenic acid (ALA) and linoleic acid – must be obtained from food or from a dietary supplement. Essential fatty acids are needed for various cellular metabolic processes and for the maintenance and function of tissues and organs. These fatty acids also are precursors to vitamins, cofactors, and derivatives, including prostaglandins, leukotrienes, thromboxanes, lipoxins, and others.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">Resolvin</span> Class of chemical compounds

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic eicosanoids.

<span class="mw-page-title-main">Essential fatty acid interactions</span>

There is a wide variety of fatty acids found in nature. Two classes of fatty acids are considered essential, the omega-3 and omega-6 fatty acids. Essential fatty acids are necessary for humans but cannot be synthesized by the body and must therefore be obtained from food. Omega-3 and omega-6 are used in some cellular signaling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and linoleic acid to their biologically active epoxides.

<span class="mw-page-title-main">Vernolic acid</span> Chemical compound

Vernolic acid is a long chain fatty acid that is monounsaturated and contains an epoxide. It is a cis epoxide derived from the C12–C13 alkene of linoleic acid. Vernolic acid was first definitively characterized in 1954 and its absolute configuration determined in 1966. It is a major component in vernonia oil, which is produced in abundance by the genera Vernonia and Euphorbia and is a potentially useful biofeedstock.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

<span class="mw-page-title-main">ALOX15</span> Lipoxygenase found in humans

ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function

<span class="mw-page-title-main">CYP2J2</span> Gene of the species Homo sapiens

Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.

<span class="mw-page-title-main">CYP2C18</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.

<span class="mw-page-title-main">CYP4A11</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities.

<span class="mw-page-title-main">Epoxide hydrolase 2</span> Protein-coding gene in the species Homo sapiens

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding diols. A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides. These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

<span class="mw-page-title-main">Epoxyeicosatetraenoic acid</span> Chemical compound

Epoxyeicosatetraenoic acids are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

References

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  2. 1 2 3 Camunas-Alberca SM, Moran-Garrido M, Sáiz J, Villaseñor A, Taha AY, Barbas C (July 2023). "The role of oxylipins and their validation as biomarkers in the clinical context". TrAC Trends in Analytical Chemistry. 164: 117065. doi: 10.1016/j.trac.2023.117065 .
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  4. 1 2 3 Liang N, Harsch BA, Zhou S, Borkowska A, Shearer GC, Kaddurah-Daouk R, et al. (January 2024). "Oxylipin transport by lipoprotein particles and its functional implications for cardiometabolic and neurological disorders" (PDF). Progress in Lipid Research. 93: 101265. doi: 10.1016/j.plipres.2023.101265 . PMID   37979798.
  5. ↑ Wolfer AM, Gaudin M, Taylor-Robinson SD, Holmes E, Nicholson JK (December 2015). "Development and Validation of a High-Throughput Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry Approach for Screening of Oxylipins and Their Precursors". Analytical Chemistry. 87 (23): 11721–11731. doi:10.1021/acs.analchem.5b02794. PMID   26501362.
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  11. ↑ Ramsden CE, Ringel A, Feldstein AE, Taha AY, MacIntosh BA, Hibbeln JR, et al. (2012). "Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 87 (4–5): 135–141. doi:10.1016/j.plefa.2012.08.004. PMC   3467319 . PMID   22959954.
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