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 enzymatic 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-inflammatory 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 anti-inflammatory 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]

References

  1. ↑ Wasternack C (October 2007). "Jasmonates: an update on biosynthesis, signal transduction and action in plant stress response, growth and development". Annals of Botany. 100 (4): 681–697. doi:10.1093/aob/mcm079. PMC   2749622 . PMID   17513307.
  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 .
  3. 1 2 3 Watrous JD, Niiranen TJ, Lagerborg KA, Henglin M, Xu YJ, Rong J, et al. (March 2019). "Directed Non-targeted Mass Spectrometry and Chemical Networking for Discovery of Eicosanoids and Related Oxylipins". Cell Chemical Biology. 26 (3): 433–442.e4. doi:10.1016/j.chembiol.2018.11.015. PMC   6636917 . PMID   30661990.
  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.
  6. ↑ Zhao J, Davis LC, Verpoorte R (June 2005). "Elicitor signal transduction leading to production of plant secondary metabolites". Biotechnology Advances. 23 (4): 283–333. doi:10.1016/j.biotechadv.2005.01.003. PMID   15848039.
  7. ↑ Bolwell GP, Bindschedler LV, Blee KA, Butt VS, Davies DR, Gardner SL, et al. (May 2002). "The apoplastic oxidative burst in response to biotic stress in plants: a three-component system". Journal of Experimental Botany. 53 (372): 1367–1376. doi:10.1093/jexbot/53.372.1367. PMID   11997382.
  8. ↑ Barquissau V, Ghandour RA, Ailhaud G, Klingenspor M, Langin D, Amri EZ, et al. (May 2017). "Control of adipogenesis by oxylipins, GPCRs and PPARs" (PDF). Biochimie. 136: 3–11. doi:10.1016/j.biochi.2016.12.012. PMID   28034718.
  9. 1 2 3 4 Gabbs M, Leng S, Devassy JG, Monirujjaman M, Aukema HM (September 2015). "Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs". Advances in Nutrition. 6 (5): 513–540. doi:10.3945/an.114.007732. PMC   4561827 . PMID   26374175.
  10. ↑ Collino S, Montoliu I, Martin FP, Scherer M, Mari D, Salvioli S, et al. (2013). "Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism". PLOS ONE. 8 (3): e56564. Bibcode:2013PLoSO...856564C. doi: 10.1371/journal.pone.0056564 . PMC   3590212 . PMID   23483888.
  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.
  12. ↑ Guyenet SJ, Carlson SE (November 2015). "Increase in adipose tissue linoleic acid of US adults in the last half century". Advances in Nutrition. 6 (6): 660–664. doi:10.3945/an.115.009944. PMC   4642429 . PMID   26567191.
  13. 1 2 Shichiri M, Adkins Y, Ishida N, Umeno A, Shigeri Y, Yoshida Y, et al. (November 2014). "DHA concentration of red blood cells is inversely associated with markers of lipid peroxidation in men taking DHA supplement". Journal of Clinical Biochemistry and Nutrition. 55 (3): 196–202. doi:10.3164/jcbn.14-22. PMC   4227822 . PMID   25411526.
  14. ↑ Biagini D, Oliveri P, Baj A, Gasperina DD, Ferrante FD, Lomonaco T, et al. (December 2023). "The effect of SARS-CoV-2 variants on the plasma oxylipins and PUFAs of COVID-19 patients" (PDF). Prostaglandins & Other Lipid Mediators. 169: 106770. doi:10.1016/j.prostaglandins.2023.106770. PMID   37633481.
  15. 1 2 Chistyakov DV, Azbukina NV, Lopachev AV, Goriainov SV, Astakhova AA, Ptitsyna EV, et al. (April 2024). "Plasma oxylipin profiles reflect Parkinson's disease stage". Prostaglandins & Other Lipid Mediators. 171: 106788. doi:10.1016/j.prostaglandins.2023.106788. PMID   37866654.
  16. ↑ Chaves-Filho AB, Diniz LS, Santos RS, Lima RS, Oreliana H, Pinto IF, et al. (November 2023). "Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis" (PDF). Free Radical Biology & Medicine. 208: 285–298. doi:10.1016/j.freeradbiomed.2023.08.019. PMID   37619957.
  17. ↑ Tans R, Bande R, van Rooij A, Molloy BJ, Stienstra R, Tack CJ, et al. (September 2020). "Evaluation of cyclooxygenase oxylipins as potential biomarker for obesity-associated adipose tissue inflammation and type 2 diabetes using targeted multiple reaction monitoring mass spectrometry". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 160: 102157. doi:10.1016/j.plefa.2020.102157. hdl: 2066/222812 . PMID   32629236.
  18. ↑ Borkowski K, Pedersen TL, Seyfried NT, Lah JJ, Levey AI, Hales CM, et al. (September 2021). "Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer's disease". Alzheimer's Research & Therapy. 13 (1): 149. doi: 10.1186/s13195-021-00893-6 . PMC   8422756 . PMID   34488866.
  19. ↑ Imig JD, Hammock BD (October 2009). "Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases". Nature Reviews. Drug Discovery. 8 (10): 794–805. doi:10.1038/nrd2875. PMC   3021468 . PMID   19794443.
  20. ↑ Wagner KM, McReynolds CB, Schmidt WK, Hammock BD (December 2017). "Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases". Pharmacology & Therapeutics. 180: 62–76. doi:10.1016/j.pharmthera.2017.06.006. PMC   5677555 . PMID   28642117.
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