The Role of Arachidonic Acid Metabolites, From Patients With Metabolic Syndrome
NCT ID: NCT02498119
Last Updated: 2016-06-21
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
12 participants
OBSERVATIONAL
2014-11-30
2016-09-30
Brief Summary
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Detailed Description
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At the molecular lever, inflammatory cytokines, fatty acid derivatives such as ceramides, diacylglycerols and reactive oxygen species (ROS), activate several serine/threonine kinases, that have emerged as important negative regulators of insulin signaling. Because of their ability to directly oxidize DNA, protein and lipid damage, ROS are believed to play a key role in the metabolic syndrome and the possible development of T2DM. It is possible that ROS and oxidative stress, induced by elevations in glucose and possibly free fatty acid levels play a key role in causing insulin resistance, and beta cell dysfunction by their ability to activate stress sensitive signaling pathways.
Lipids as signaling intermediates encompass a vast range of molecules with distinct function. The characteristics includes, lipid bodies(LB) are sites for the production of inflammatory mediators and LB within inflammatory cells contain arachidonyl lipids which serve as precursors for eicosanoids. In addition, formation of LB within inflammatory macrophages was positively correlated with augmented increase in prostaglandin E2 (PGE2) in changes. LB also could function as a draining compartment to rapidly uptake and re-acetylate free arachidonic acid with the potentially detrimental outcomes for the host cell.
Macrophage from cells with lipid bodies involves complex and multi step mechanisms that depend on different signaling pathways regulating lipid influx, metabolism storage and mobilization. In view of these clues the investigators have reason to believe that organic anion transporters might be resident or upon stimulation trans located to lipid bodies in order to export the newly synthesized lipid mediators into the cytoplasmic space. Once outside the lipid bodies the eicosanoids can exert intracrine functions or be exported to plasma membrane resident transporters to the extracellular space. Free fatty acids have adverse effects on the mitochondrial function including uncoupling of oxidative phosphorylation and the generation of ROS. Beta cell lipotoxicity has an amplifying effect only if mediated by concurrent hyperglycemia. The association of obesity, fatty acids and oxidative stress with insulin action clearly merits further attention with particular focus on the molecular mechanism.
Conditions
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Study Design
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PROSPECTIVE
Study Groups
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Normal
Patient sample within the normal range of blood results.
No interventions assigned to this group
Abnormal
Patient sample from freshly diagnosed Type 2 Diabetes Mellitus.
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* Patient diagnosed with Type 2 Diabetes Mellitus within 1 year
Exclusion Criteria
* Patients with uncontrolled diabetes, heart failure and sepsis
18 Years
60 Years
ALL
Yes
Sponsors
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University of Malaya
OTHER
Responsible Party
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Gracie Ong @ Gracie Ong Siok Yan
Senior Consultant
Principal Investigators
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Gracie Ong Siok Yan
Role: PRINCIPAL_INVESTIGATOR
Senior Consultant
Locations
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University Malaya Medical Center (UMMC)
Petaling Jaya, Kuala Lumpur, Malaysia
Countries
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Central Contacts
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Facility Contacts
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References
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Melo RC, D'Avila H, Wan HC, Bozza PT, Dvorak AM, Weller PF. Lipid bodies in inflammatory cells: structure, function, and current imaging techniques. J Histochem Cytochem. 2011 May;59(5):540-56. doi: 10.1369/0022155411404073. Epub 2011 Mar 23.
Melo RC, Paganoti GF, Dvorak AM, Weller PF. The internal architecture of leukocyte lipid body organelles captured by three-dimensional electron microscopy tomography. PLoS One. 2013;8(3):e59578. doi: 10.1371/journal.pone.0059578. Epub 2013 Mar 26.
Tauchi-Sato K, Ozeki S, Houjou T, Taguchi R, Fujimoto T. The surface of lipid droplets is a phospholipid monolayer with a unique Fatty Acid composition. J Biol Chem. 2002 Nov 15;277(46):44507-12. doi: 10.1074/jbc.M207712200. Epub 2002 Sep 6.
Dichlberger A, Schlager S, Lappalainen J, Kakela R, Hattula K, Butcher SJ, Schneider WJ, Kovanen PT. Lipid body formation during maturation of human mast cells. J Lipid Res. 2011 Dec;52(12):2198-2208. doi: 10.1194/jlr.M019737. Epub 2011 Oct 4.
Krahmer N, Farese RV Jr, Walther TC. Balancing the fat: lipid droplets and human disease. EMBO Mol Med. 2013 Jul;5(7):973-83. doi: 10.1002/emmm.201100671. Epub 2013 Jun 6.
Hapala I, Marza E, Ferreira T. Is fat so bad? Modulation of endoplasmic reticulum stress by lipid droplet formation. Biol Cell. 2011 Jun;103(6):271-85. doi: 10.1042/BC20100144.
Beller M, Thiel K, Thul PJ, Jackle H. Lipid droplets: a dynamic organelle moves into focus. FEBS Lett. 2010 Jun 3;584(11):2176-82. doi: 10.1016/j.febslet.2010.03.022. Epub 2010 Mar 18.
Brasaemle DL. Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. J Lipid Res. 2007 Dec;48(12):2547-59. doi: 10.1194/jlr.R700014-JLR200. Epub 2007 Sep 18.
Goodman JM. The gregarious lipid droplet. J Biol Chem. 2008 Oct 17;283(42):28005-9. doi: 10.1074/jbc.R800042200. Epub 2008 Jul 8. No abstract available.
Blaner WS, O'Byrne SM, Wongsiriroj N, Kluwe J, D'Ambrosio DM, Jiang H, Schwabe RF, Hillman EM, Piantedosi R, Libien J. Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage. Biochim Biophys Acta. 2009 Jun;1791(6):467-73. doi: 10.1016/j.bbalip.2008.11.001. Epub 2008 Nov 24.
Dvorak AM, Dvorak HF, Peters SP, Shulman ES, MacGlashan DW Jr, Pyne K, Harvey VS, Galli SJ, Lichtenstein LM. Lipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells. J Immunol. 1983 Dec;131(6):2965-76.
Dvorak AM, Hammel I, Schulman ES, Peters SP, MacGlashan DW Jr, Schleimer RP, Newball HH, Pyne K, Dvorak HF, Lichtenstein LM, et al. Differences in the behavior of cytoplasmic granules and lipid bodies during human lung mast cell degranulation. J Cell Biol. 1984 Nov;99(5):1678-87. doi: 10.1083/jcb.99.5.1678.
Triggiani M, Oriente A, Marone G. Differential roles for triglyceride and phospholipid pools of arachidonic acid in human lung macrophages. J Immunol. 1994 Feb 1;152(3):1394-403.
Yu W, Bozza PT, Tzizik DM, Gray JP, Cassara J, Dvorak AM, Weller PF. Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies. Am J Pathol. 1998 Mar;152(3):759-69.
Triggiani M, Oriente A, Seeds MC, Bass DA, Marone G, Chilton FH. Migration of human inflammatory cells into the lung results in the remodeling of arachidonic acid into a triglyceride pool. J Exp Med. 1995 Nov 1;182(5):1181-90. doi: 10.1084/jem.182.5.1181.
Silva AR, Pacheco P, Vieira-de-Abreu A, Maya-Monteiro CM, D'Alegria B, Magalhaes KG, de Assis EF, Bandeira-Melo C, Castro-Faria-Neto HC, Bozza PT. Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon. Biochim Biophys Acta. 2009 Nov;1791(11):1066-75. doi: 10.1016/j.bbalip.2009.06.004. Epub 2009 Jun 30.
Bozza PT, Bakker-Abreu I, Navarro-Xavier RA, Bandeira-Melo C. Lipid body function in eicosanoid synthesis: an update. Prostaglandins Leukot Essent Fatty Acids. 2011 Nov;85(5):205-13. doi: 10.1016/j.plefa.2011.04.020. Epub 2011 May 12.
Related Links
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The internal architecture of leukocyte lipid body organelles captured by three-dimensional electron microscopy tomography
Balancing the fat: lipid droplets and human disease
Is fat so bad? Modulation of endoplasmic reticulum stress by lipid droplet formation
a dynamic organelle moves into focus
The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis
The gregarious lipid droplet
Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage
Lipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells
Differences in the behavior of cytoplasmic granules and lipid bodies during human lung mast cell degranulation
Differential roles for triglyceride and phospholipid pools of arachidonic acid in human lung macrophages
Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies
Migration of human inflammatory cells into the lung results in the remodeling of arachidonic acid into a triglyceride pool
Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a monocyte chemotactic protein 1/ chemokine ligand 2 (MCP-1/CCL2) regulated phenomenon
Lipid body function in eicosanoids synthesis : An update
Other Identifiers
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RG291-14AFR
Identifier Type: -
Identifier Source: org_study_id
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