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Lee, A. G., J. M. East, and R. J. Froud. "Are essential fatty acids essential for membrane function?" Progress in Lipid Research 25 (January 1986): 41–46. http://dx.doi.org/10.1016/0163-7827(86)90009-3.
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Haag, Marianne. "Essential Fatty Acids and the Brain." Canadian Journal of Psychiatry 48, no. 3 (April 2003): 195–203. http://dx.doi.org/10.1177/070674370304800308.
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Objective: To review the role of essential fatty acids in brain membrane function and in the genesis of psychiatric disease. Method: Medline databases were searched for published articles with links among the following key words: essential fatty acids, omega-3 fatty acids, docosahexanoic acid, eicosapentanoic acid, arachidonic acid, neurotransmission, phospholipase A2, depression, schizophrenia, mental performance, attention-deficit hyperactivity disorder, and Alzheimer's disease. Biochemistry textbooks were consulted on the role of fatty acids in membrane function, neurotransmission, and eicosanoid formation. The 3-dimensional structures of fatty acids were obtained from the Web site of the Biochemistry Department, University of Arizona (2001). Results: The fatty acid composition of neuronal cell membrane phospholipids reflects their intake in the diet. The degree of a fatty acid's desaturation determines its 3-dimensional structure and, thus, membrane fluidity and function. The ratio between omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), in particular, influences various aspects of serotoninergic and catecholaminergic neurotransmission, as shown by studies in animal models. Phospholipase A2 (PLA2) hydrolyzes fatty acids from membrane phospholipids: liberated omega-6 PUFAs are metabolized to prostaglandins with a higher inflammatory potential, compared with those generated from the omega-3 family. Thus the activity of PLA2 coupled with membrane fatty acid composition may play a central role in the development of neuronal dysfunction. Intervention trials in human subjects show that omega-3 fatty acids have possible positive effects in the treatment of various psychiatric disorders, but more data are needed to make conclusive directives in this regard. Conclusion: The ratio of membrane omega-3 to omega-6 PUFAs can be modulated by dietary intake. This ratio influences neurotransmission and prostaglandin formation, processes that are vital in the maintenance of normal brain function.
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Dessì, Mariarita, Annalisa Noce, Pierfrancesco Bertucci, Simone Manca di Villahermosa, Rossella Zenobi, Veronica Castagnola, Eliana Addessi, and Nicola Di Daniele. "Atherosclerosis, Dyslipidemia, and Inflammation: The Significant Role of Polyunsaturated Fatty Acids." ISRN Inflammation 2013 (May 12, 2013): 1–13. http://dx.doi.org/10.1155/2013/191823.
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Phospholipids play an essential role in cell membrane structure and function. The length and number of double bonds of fatty acids in membrane phospholipids are main determinants of fluidity, transport systems, activity of membrane-bound enzymes, and susceptibility to lipid peroxidation. The fatty acid profile of serum lipids, especially the phospholipids, reflects the fatty acid composition of cell membranes. Moreover, long-chain n-3 polyunsatured fatty acids decrease very-low-density lipoprotein assembly and secretion reducing triacylglycerol production. N-6 and n-3 polyunsatured fatty acids are the precursors of signalling molecules, termed “eicosanoids,” which play an important role in the regulation of inflammation. Eicosanoids derived from n-6 polyunsatured fatty acids have proinflammatory actions, while eicosanoids derived from n-3 polyunsatured fatty acids have anti-inflammatory ones. Previous studies showed that inflammation contributes to both the onset and progression of atherosclerosis: actually, atherosclerosis is predominantly a chronic low-grade inflammatory disease of the vessel wall. Several studies suggested the relationship between long-chain n-3 polyunsaturated fatty acids and inflammation, showing that fatty acids may decrease endothelial activation and affect eicosanoid metabolism.
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Condray, Ruth, Jeffrey K. Yao, Stuart R. Steinhauer, Daniel P. van Kammen, Ravinder D. Reddy, and Lisa A. Morrow. "Semantic memory in schizophrenia: Association with cell membrane essential fatty acids." Schizophrenia Research 106, no. 1 (November 2008): 13–28. http://dx.doi.org/10.1016/j.schres.2008.03.009.
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Mukerjee, Souvik, Abdulaziz S. Saeedan, Mohd Nazam Ansari, and Manjari Singh. "Polyunsaturated Fatty Acids Mediated Regulation of Membrane Biochemistry and Tumor Cell Membrane Integrity." Membranes 11, no. 7 (June 28, 2021): 479. http://dx.doi.org/10.3390/membranes11070479.
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Particular dramatic macromolecule proteins are responsible for various cellular events in our body system. Lipids have recently recognized a lot more attention of scientists for understanding the relationship between lipid and cellular function and human health However, a biological membrane is formed with a lipid bilayer, which is called a P–L–P design. Our body system is balanced through various communicative signaling pathways derived from biological membrane proteins and lipids. In the case of any fatal disease such as cancer, the biological membrane compositions are altered. To repair the biological membrane composition and prevent cancer, dietary fatty acids, such as omega-3 polyunsaturated fatty acids, are essential in human health but are not directly synthesized in our body system. In this review, we will discuss the alteration of the biological membrane composition in breast cancer. We will highlight the role of dietary fatty acids in altering cellular composition in the P–L–P bilayer. We will also address the importance of omega-3 polyunsaturated fatty acids to regulate the membrane fluidity of cancer cells.
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Glick, Norris R., and Milton H. Fischer. "The Role of Essential Fatty Acids in Human Health." Journal of Evidence-Based Complementary & Alternative Medicine 18, no. 4 (May 22, 2013): 268–89. http://dx.doi.org/10.1177/2156587213488788.
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Fatty acid research began about 90 years ago but intensified in recent years. Essential fatty acids (linoleic and α-linolenic) must come from diet. Other fatty acids may come from diet or may be synthesized. Fatty acids are major components of cell membrane structure, modulate gene transcription, function as cytokine precursors, and serve as energy sources in complex, interconnected systems. It is increasingly apparent that dietary fatty acids influence these vital functions and affect human health. While the strongest evidence for influence is found in cardiovascular disease and mental health, many additional conditions are affected. Problematic changes in the fatty acid composition of human diet have also taken place over the last century. This review summarizes current understanding of the pervasive roles of essential fatty acids and their metabolites in human health.
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Peet, Malcolm, Jon Laugharne, N. Rangarajan, David Horrobin, and Gavin Reynolds. "Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients." Journal of Psychiatric Research 29, no. 3 (May 1995): 227–32. http://dx.doi.org/10.1016/0022-3956(95)00001-l.
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Tranchant, T., P. Besson, C. Hoinard, M. Pinault, J. M. Alessandri, J. Delarue, C. Couet, and J. Goré. "Long-term supplementation of culture medium with essential fatty acids alters α-linolenic acid uptake in Caco-2 clone TC7." Canadian Journal of Physiology and Pharmacology 76, no. 6 (June 1, 1998): 621–29. http://dx.doi.org/10.1139/y98-071.
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We investigated the influence of four different culture media: 20% fetal bovine serum (FBS), 5% FBS, 5% FBS supplemented with 10 mg·L-1 linoleic acid (18:2(n-6)) or alpha-linolenic acid (18:3(n-3)) on alpha-linolenic acid apical uptake in clone TC7 of human intestinal Caco-2 cell line. Neither cellular viability nor cell monolayer integrity and permeability were altered by the four culture conditions. Our results show that the different culture media led to changes in alpha-linolenic acid maximal rate of uptake (Vmax) but did not alter the apparent transport constant (Km). Reducing FBS concentration from 20% to 5% increased significantly the rate of alpha-linolenic acid uptake, which was further increased by supplementation of the medium with 18:2(n-6) or 18:3(n-3). Supplementation with essential fatty acids led to a marked enrichment of brush-border membrane phospholipids in polyunsaturated fatty acids of the corresponding series and decreased significantly the levels of monounsaturated fatty acids. Saturated fatty acids, unsaturation index, and cholesterol / fatty acid ratios were unchanged. No clear relation could be established between the changes in membrane lipid composition and the alterations of alpha-linolenic acid uptake. These results indicate a weak influence of membrane lipid composition in the modulation of the uptake. Therefore, the increase of uptake following long-term supplementation of TC7 cells with essential fatty acids could be attributed to an increase of the expression of membrane protein(s) involved in the apical uptake of long-chain fatty acids. This remains to be established.Key words: fatty acid intestinal absorption, Caco-2 cells, membrane fatty acid transport protein, membrane phospholipid fatty acid composition.
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Uauy, Ricardo, Patricia Mena, and Cecilia Rojas. "Essential fatty acids in early life: structural and functional role." Proceedings of the Nutrition Society 59, no. 1 (February 2000): 3–15. http://dx.doi.org/10.1017/s0029665100000021.
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Essential fatty acids (EFA) are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LCPUFA). These fatty acids serve as specific precursors for eicosanoids that regulate numerous cell and organ functions. Results from animal and recent human studies support the essential nature of n-3 EFA in addition to the well-established role of n-6 EFA for human subjects, particularly in early life. The most significant effects relate to neural development and maturation of sensory systems. Recent studies using stable-isotope-labelled tracers demonstrate that even preterm infants are able to form arachidonic acid (AA) and docosahexaenoic acid (DHA), but that synthesis is extremely low. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation, and retinal and nervous system development. Regulation of gene expression by LCPUFA occurs at the transcriptional level and is mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the steroid hormone receptor family. Two types of polyunsaturated fatty acid responsive transcription factors have been characterized, the peroxisome proliferator-activated receptor (PPAR) and the hepatic nuclear factor 4α. DHA also has significant effects on photoreceptor membranes involved in the signal transduction process, rhodopsin activation, and rod and cone development. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oils, sources of LCPUFA, results in increased blood levels of DHA and AA, as well as an associated improvement in visual function in formula-fed premature infants to match that of human milk-fed infant. Recent clinical trials convincingly support LCPUFA supplementation of preterm infant formulations and possibly term formula to mimic human milk composition.
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Rodríguez-Vargas, Sonia, Alicia Sánchez-García, Jose Manuel Martínez-Rivas, Jose Antonio Prieto, and Francisca Randez-Gil. "Fluidization of Membrane Lipids Enhances the Tolerance of Saccharomyces cerevisiae to Freezing and Salt Stress." Applied and Environmental Microbiology 73, no. 1 (October 27, 2006): 110–16. http://dx.doi.org/10.1128/aem.01360-06.
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ABSTRACT Unsaturated fatty acids play an essential role in the biophysical characteristics of cell membranes and determine the proper function of membrane-attached proteins. Thus, the ability of cells to alter the degree of unsaturation in their membranes is an important factor in cellular acclimatization to environmental conditions. Many eukaryotic organisms can synthesize dienoic fatty acids, but Saccharomyces cerevisiae can introduce only a single double bond at the Δ9 position. We expressed two sunflower (Helianthus annuus) oleate Δ12 desaturases encoded by FAD2-1 and FAD2-3 in yeast cells of the wild-type W303-1A strain (trp1) and analyzed their effects on growth and stress tolerance. Production of the heterologous desaturases increased the content of dienoic fatty acids, especially 18:2Δ9,12, the unsaturation index, and the fluidity of the yeast membrane. The total fatty acid content remained constant, and the level of monounsaturated fatty acids decreased. Growth at 15°C was reduced in the FAD2 strains, probably due to tryptophan auxotrophy, since the trp1 (TRP1) transformants that produced the sunflower desaturases grew as well as the control strain did. Our results suggest that changes in the fluidity of the lipid bilayer affect tryptophan uptake and/or the correct targeting of tryptophan transporters. The expression of the sunflower desaturases, in either Trp+ or Trp− strains, increased NaCl tolerance. Production of dienoic fatty acids increased the tolerance to freezing of wild-type cells preincubated at 30°C or 15°C. Thus, membrane fluidity is an essential determinant of stress resistance in S. cerevisiae, and engineering of membrane lipids has the potential to be a useful tool of increasing the tolerance to freezing in industrial strains.
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Chen, Jinchao, Yunxia Li, Zhiru Tang, and Zhihong Sun. "Regulatory Functions of Fatty Acids with Different Chain Lengths on the Intestinal Health in Pigs and Relative Signaling Pathways." Current Protein & Peptide Science 20, no. 7 (June 27, 2019): 674–82. http://dx.doi.org/10.2174/1389203720666190514120023.
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Intestines are not only major organs for nutrient digestion and absorption, but are also the largest immune organ in pigs. They are essential for maintaining the health and growth of piglets. Fatty acids, including short-chain fatty acids, medium-chain fatty acids, and long-chain polyunsaturated fatty acids, are important nutrients; they are a major energy source, important components of the cell membrane, metabolic substrates in many biochemical pathways, cell-signaling molecules, and play role as immune modulators. Research has shown that fatty acids exert beneficial effects on intestinal health in animal models and clinical trials. The objective of this review is to give a clear understanding of the regulatory effects of fatty acids of different chain lengths on intestinal health in pigs and their signaling pathways, providing scientific reference for developing a feeding technique to apply fatty acids to piglet diets.
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Ganga, R., L. Tort, L. Acerete, D. Montero, and M. S. Izquierdo. "Modulation of ACTH-induced cortisol release by polyunsaturated fatty acids in interrenal cells from gilthead seabream, Sparus aurata." Journal of Endocrinology 190, no. 1 (July 2006): 39–45. http://dx.doi.org/10.1677/joe.1.06770.
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Highly unsaturated fatty acids are essential components of cellular membranes of vertebrates and can modulate physiological processes, including membrane transport, receptor function and enzymatic activities. In gilthead sea bream, dietary deficiencies of essential fatty acids of marine fish raise the basal cortisol levels and alter the pattern of cortisol release after stress. The aim of the present study was to clarify the effect of different essential fatty acids on adrenocorticotropic hormone (ACTH)-induced cortisol production and release in fish, through in vitro studies of sea bream interrenal cells maintained in superfusion and incubated with different types of fatty acids and eicosanoid production inhibitors. Results showed the first evidence of the effect of certain fatty acids on cortisol production by ACTH-stimulated interrenal cells in fish. Both arachidonic acid (ARA) and particularly eicosapentaenoic acid (EPA) promoted cortisol production in sea bream interrenal cells. Moreover, incubation with indometacin (INDO) reduced the increased cortisol production induced by EPA and ARA, suggesting mediation by their cyclooxygenase-derived products. Docosahexaenoic acid stimulated cortisol production to a lesser extent than that caused by EPA or ARA, but the inhibitory effect of INDO was not as marked as it was for the other fatty acids. In contrast, supplementation with dihomogammalinoleic acid reduced cortisol production, denoting the inhibitor effect of this fatty acid in cortisol secretion.
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Bianchetti, Giada, Salome Azoulay-Ginsburg, Nimrod Yosef Keshet-Levy, Aviv Malka, Sofia Zilber, Edward E. Korshin, Shlomo Sasson, Marco De Spirito, Arie Gruzman, and Giuseppe Maulucci. "Investigation of the Membrane Fluidity Regulation of Fatty Acid Intracellular Distribution by Fluorescence Lifetime Imaging of Novel Polarity Sensitive Fluorescent Derivatives." International Journal of Molecular Sciences 22, no. 6 (March 18, 2021): 3106. http://dx.doi.org/10.3390/ijms22063106.
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Free fatty acids are essential structural components of the cell, and their intracellular distribution and effects on membrane organelles have crucial roles in regulating the metabolism, development, and cell cycle of most cell types. Here we engineered novel fluorescent, polarity-sensitive fatty acid derivatives, with the fatty acid aliphatic chain of increasing length (from 12 to 18 carbons). As in the laurdan probe, the lipophilic acyl tail is connected to the environmentally sensitive dimethylaminonaphthalene moiety. The fluorescence lifetime imaging analysis allowed us to monitor the intracellular distribution of the free fatty acids within the cell, and to simultaneously examine how the fluidity and the microviscosity of the membrane environment influence their localization. Each of these probes can thus be used to investigate the membrane fluidity regulation of the correspondent fatty acid intracellular distribution. We observed that, in PC-12 cells, fluorescent sensitive fatty acid derivatives with increased chain length compartmentalize more preferentially in the fluid regions, characterized by a low microviscosity. Moreover, fatty acid derivatives with the longest chain compartmentalize in lipid droplets and lysosomes with characteristic lifetimes, thus making these probes a promising tool for monitoring lipophagy and related events.
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Rémita, Samy. "De la peroxydation lipidique radioinduite : les facteurs déterminant l'oxydabilité des lipides." Canadian Journal of Physiology and Pharmacology 79, no. 2 (February 1, 2001): 144–53. http://dx.doi.org/10.1139/y00-091.
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Lipids are the essential components of cell membranes and lipoproteins. Their peroxidation plays an important role in numerous pathologies in which oxidative stress is involved. Lipid peroxidation occurs through a chain reaction that contributes to membrane damage in cells. It results in the conversion of fatty acids to polar hydroperoxides and leads to the breakdown or malfunction of the membrane. Lipids are amphiphilic molecules that aggregate in aqueous solutions into micelles and liposoms. The effect of this structural organization is significant in studies of radiation-induced peroxidation damage in highly ordered biological systems such as biological membranes. In this paper, a synthesis of the data concerning radioinduced lipid peroxidation is completed by an original review of the different parameters that determine lipid oxidizability. In addition, the influence of lipid aggregation and the effect of molecular packing are discussed.Key words: radiolysis, peroxidation, lipids, fatty acids.
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Todorović, Zoran, Siniša Đurašević, Maja Stojković, Ilijana Grigorov, Slađan Pavlović, Nebojša Jasnić, Tomislav Tosti, Jelica Bjekić Macut, Christoph Thiemermann, and Jelena Đorđević. "Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury." International Journal of Molecular Sciences 22, no. 6 (March 10, 2021): 2798. http://dx.doi.org/10.3390/ijms22062798.
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Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.
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Burt, J. M., K. D. Massey, and B. N. Minnich. "Uncoupling of cardiac cells by fatty acids: structure-activity relationships." American Journal of Physiology-Cell Physiology 260, no. 3 (March 1, 1991): C439—C448. http://dx.doi.org/10.1152/ajpcell.1991.260.3.c439.
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The permeability and conductance of gap junctions between pairs of neonatal rat heart cells were rapidly and reversibly decreased by oleic acid in a dose- and time-dependent manner. Other unsaturated fatty acids (C-18: cis 6, 9, or 11, and C-18, 16, and 14, cis 9), saturated fatty acids (C-10, 12, and 14), and saturated fatty alcohols (C-8, 10, and 12) also caused uncoupling. The most effective compounds of the unsaturated and saturated fatty acid and saturated fatty alcohol series caused essentially complete uncoupling at comparable aqueous concentrations. However, oleic acid uncoupled cells at membrane concentrations as low as 1 mol%, whereas decanoic acid required upwards of 35 mol%. The channels that support the action potential remained functional at these same membrane concentrations. The data are discussed in terms of the possible mechanism by which these compounds cause uncoupling and the possible role of uncoupling by nonesterified free fatty acids in the initiation of arrhythmias during and after ischemic insults.
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Dodge, John A., Jacqueline M. Custance, Mary C. Goodchild, Sheena C. Laing, and Merle Vaughan. "Paradoxical effects of essential fatty acid supplementation on lipid profiles and sweat electrolytes in cystic fibrosis." British Journal of Nutrition 63, no. 2 (March 1990): 259–71. http://dx.doi.org/10.1079/bjn19900113.
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Supplements of evening primrose oil (Oenothera biennis), which contains at least 72% linoleic (18:2n−6) and 7% γ-linolenic (18:3 n−6) acids (expressed as % fatty acid methyl esters) were given to sixteen cystic fibrosis patients for a period of 12 months. Clinical observations showed no significant changes in patients' weights or respiratory function throughout. Linoleic acid levels in plasma and erythrocyte membranes increased significantly during the first 6 months but this increase was not sustained at its initial level. After supplementation was discontinued reversion to baseline (low) levels occurred within 4 months. Levels of plasma prostaglandins (PG) and urinary PG metabolites varied among individuals over a wide range, and urinary PGF2α metabolites fell during the supplementation. There was a significant fall in sweat sodium concentrations after 6 weeks of supplementation, but sweat chloride was unchanged. It is not known whether the effect of essential fatty acids on sweat Na+ reflects changes in cell membrane conformation or if there is a direct effect on Na+ pump activity.
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Radovic, Branislav, Elma Aflaki, and Dagmar Kratky. "Adipose triglyceride lipase in immune response, inflammation, and atherosclerosis." Biological Chemistry 393, no. 9 (September 1, 2012): 1005–11. http://dx.doi.org/10.1515/hsz-2012-0192.
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Abstract Consistent with its central importance in lipid and energy homeostasis, lipolysis occurs in essentially all tissues and cell types, including macrophages. The hydrolytic cleavage of triacylglycerol by adipose triglyceride lipase (ATGL) generates non-esterified fatty acids, which are subsequently used as essential precursors for lipid and membrane synthesis, mediators in cell signaling processes or as energy substrate in mitochondria. This review summarizes the current knowledge concerning the consequences of ATGL deficiency in macrophages with particular emphasis on macrophage (dys)-function, apoptosis, and atherosclerosis.
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Schenkel, Laila Cigana, and Marica Bakovic. "Formation and Regulation of Mitochondrial Membranes." International Journal of Cell Biology 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/709828.
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Mitochondrial membrane phospholipids are essential for the mitochondrial architecture, the activity of respiratory proteins, and the transport of proteins into the mitochondria. The accumulation of phospholipids within mitochondria depends on a coordinate synthesis, degradation, and trafficking of phospholipids between the endoplasmic reticulum (ER) and mitochondria as well as intramitochondrial lipid trafficking. Several studies highlight the contribution of dietary fatty acids to the remodeling of phospholipids and mitochondrial membrane homeostasis. Understanding the role of phospholipids in the mitochondrial membrane and their metabolism will shed light on the molecular mechanisms involved in the regulation of mitochondrial function and in the mitochondrial-related diseases.
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Suh, M., A. A. Wierzbicki, E. Lien, and M. T. Clandinin. "Relationship between dietary supply of long-chain fatty acids and membrane composition of long- and very long chain essential fatty acids in developing rat photoreceptors." Lipids 31, no. 1 (January 1996): 61–64. http://dx.doi.org/10.1007/bf02522412.
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Nguyen, Long Nam, Attila Gacser, and Joshua D. Nosanchuk. "The Stearoyl-Coenzyme A Desaturase 1 Is Essential for Virulence and Membrane Stress inCandida parapsilosisthrough Unsaturated Fatty Acid Production." Infection and Immunity 79, no. 1 (October 25, 2010): 136–45. http://dx.doi.org/10.1128/iai.00753-10.
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ABSTRACTUnsaturated fatty acids (UFA) are essential components of cells. InSaccharomyces cerevisiae, stearoyl-coenzyme A (CoA) desaturase 1 (OLE1) affects cell viability through the regulation of oleic (18:1) or palmitoleic (16:1) acid production. In this study, we used a targeted gene deletion approach to determine the impact ofOLE1on the emerging human pathogenic fungusCandida parapsilosis. We found that the deletion ofOLE1resulted in an auxotrophic yeast strain (designatedOLE1KO) that required unsaturated fatty acids for growth but not saturated fatty acids. Additionally, the production of UFA byOLE1KO yeast cells was markedly reduced, suggesting that Ole1 is essential for UFA production. In contrast to wild-typeC. parapsilosis, which produced pseudohyphal growth on UFA-supplemented medium agar, pseudohyphal formation in theOLE1KO cells was severely impaired, suggesting that Ole1 regulates morphology. Furthermore, theOLE1KO cells were hypersensitive to various stress-inducing factors, such as salts, SDS, and H2O2, especially at the physiological temperature. The results indicate thatOLE1is essential for the stress response, perhaps through the production of UFA for cell membrane biosynthesis. TheOLE1KO cells also were hypersensitive to human and fetal bovine serum, suggesting that targeting Ole1 could suppress the dissemination of yeast cells in the bloodstream. Murine-like macrophage J774.16 more efficiently killed theOLE1KO yeasts, and significantly larger amounts of nitric oxide were detected in cocultures of macrophages andOLE1KO cells than with wild-type or heterozygous strains. Moreover, the disruption ofOLE1significantly reduced fungal virulence in systemic murine infection. Taken together, these results demonstrate that Ole1 regulates the pathobiology ofC. parapsilosisvia UFA and that theOLE1pathway is a promising antifungal target.
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Pohl, Jürgen, Axel Ring, Thomas Herrmann, and Wolfgang Stremmel. "New concepts of cellular fatty acid uptake: role of fatty acid transport proteins and of caveolae." Proceedings of the Nutrition Society 63, no. 2 (May 2004): 259–62. http://dx.doi.org/10.1079/pns2004341.
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Efficient uptake and channelling of long-chain fatty acids (LCFA) are critical cell functions. Evidence is emerging that proteins are important mediators of LCFA-trafficking into cells and various proteins have been suggested to be involved in this process. Amongst these proteins is a family of membrane-associated proteins termed fatty acid transport proteins (FATP). So far six members of this family, designated FATP 1–6, have been characterized. FATP 1, 2 and 6 show a highly-conserved AMP-binding region that participates in the activation of very-long-chain fatty acids (VLCFA) to form their acyl-CoA derivatives. The mechanisms by which FATP mediate LCFA uptake are not well understood, but several studies provide evidence that uptake of LCFA across cellular membranes is closely linked to acyl-CoA synthetase activity. It is proposed that FATP indirectly enhance LCFA uptake by activating VLCFA to their CoA esters, which are required to maintain the typical structure of lipid rafts in cellular membranes. Recent work has shown that the structural integrity of lipid rafts is essential for cellular LCFA uptake. This effect might be exerted by proteins, e.g. caveolin-1 and FAT/CD36, that use lipid rafts as platforms and bind or transport LCFA. The proposed molecular mechanisms await further experimental investigation.
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Reddy, R. D., M. S. Keshavan, and J. K. Yao. "Reduced Red Blood Cell Membrane Essential Polyunsaturated Fatty Acids in First Episode Schizophrenia at Neuroleptic-Naive Baseline." Schizophrenia Bulletin 30, no. 4 (January 1, 2004): 901–11. http://dx.doi.org/10.1093/oxfordjournals.schbul.a007140.
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Suzumura, Ayana, Ryo Terao, and Hiroki Kaneko. "Protective Effects and Molecular Signaling of n-3 Fatty Acids on Oxidative Stress and Inflammation in Retinal Diseases." Antioxidants 9, no. 10 (September 26, 2020): 920. http://dx.doi.org/10.3390/antiox9100920.
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Oxidative stress and inflammation play crucial roles in the development and progression of retinal diseases. Retinal damage by various etiologies can result in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). n-3 fatty acids are essential fatty acids and are necessary for homeostasis. They are important retinal membrane components and are involved in energy storage. n-3 fatty acids also have antioxidant and anti-inflammatory properties, and their suppressive effects against ROP, DR, and AMD have been previously evaluated. α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their metabolites have been shown to alleviate retinal oxidative stress and inflammation involving various biological signaling pathways. In this review, we summarize the current understanding of the n-3 fatty acids effects on the mechanisms of these retinal diseases and how they exert their therapeutic effects, focusing on ALA, EPA, DHA, and their metabolites. This knowledge may provide new remedial strategies for n-3 fatty acids in the prevention and treatment of retinal diseases associated with oxidative stress and inflammation.
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Cheng, Xiang, Feng Geng, Yaogang Zhong, Zhihua Tian, Meixia Pan, Chunming Cheng, Craig Horbinski, Xiaokui Mo, Xianlin Han, and Deliang Guo. "CBMT-29. PROMOTING FATTY ACID STORAGE BY DIACYLGLYCEROL-ACYLTRANSFERASE 1 PROTECTS GLIOBLASTOMA AGAINST OXIDATIVE STRESS AND MAINTAINS LIPID HOMEOSTASIS FOR RAPID TUMOR GROWTH." Neuro-Oncology 21, Supplement_6 (November 2019): vi39. http://dx.doi.org/10.1093/neuonc/noz175.151.
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Abstract Fatty acids are essential building blocks and energy substrates of lipids in cells. They constitute the major structural components of membrane lipids, i.e., glycerophospholipids and sphingolipids, and also serve as an important energy resource. Whereas excess fatty acids or dysregulation of fatty acid metabolism causes lipotoxicity, leading to severe cell damage. We previously identified that lipid metabolism is dramatically altered in glioblastoma (GBM), especially fatty acid synthesis, which is greatly elevated in various types of cancers. However, how tumor cells prevent excessive fatty acids accumulation from inducing lipotoxicity has rarely been studied. We recently identified that GBM greatly upregulates diacylglycerol-acyltransferase 1 (DGAT1) to direct excess fatty acids into triglycerides and lipid droplets to prevent oxidative stress. Inhibiting DGAT1 disrupts lipid homeostasis and shifts excessive fatty acids moving into mitochondria for oxidation, resulting in a high level of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release and apoptosis. Inhibiting carnitine palmitoyltransferase to reduce fatty acids shuttling into mitochondria significantly decreases ROS and rescues cell death caused by DGAT1 inhibition. Xenograft models show that genetic or pharmacological inhibition of DGAT1 blocks lipid droplet formation, induces tumor cell apoptosis and markedly suppresses GBM tumor growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating excess fatty acids storage. Our data further show that targeting DGAT1 specifically induces lipotoxicity in tumor cells, while sparing normal brain, which is a very promising therapeutic strategy antagonizing GBM and has a high potential to shift current paradigm in treating GBM.
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Innis, Sheila M. "Essential fatty acid requirements in human nutrition." Canadian Journal of Physiology and Pharmacology 71, no. 9 (September 1, 1993): 699–706. http://dx.doi.org/10.1139/y93-104.
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Arachidonic acid (20:4ω−6) and docosahexaenoic acid (22:6ω−3) are major acyl components of cell membrane phospholipids, and are particularly enriched in the nonmyelin membranes of the central nervous system. Dietary deficiency of linoleic acid (18:2ω−6) and linolenic acid (18:3ω−3) during development has been shown to result in reduced levels of 20:4ω−6 and 22:6ω−3 in the developing central nervous system, and this has been associated with altered learning behaviour and visual function. Synthesis of 20:4ω−6 and 22:6ω−3 depends on the dietary intake of 18:2ω−6 and 18:3ω−3, respectively, and the activity of the fatty acid desaturase–elongase enzymes. Oxidation of 18:2ω−6 and 18:3ω−3 for energy, or direct acylation of 18:2ω−6 into triglycerides, cholesteryl esters, and phospholipids, could also influence the amount of 20:4ω−6 and 22:6ω−3 formed. The tissue levels of 20:4ω−6 and 22:6ω−3, or other (ω − 6) and (ω − 3) fatty acids, compatible with optimum growth and development or health are not known. The amount of preformed 22:6ω−3 in the diet of adults, infants fed various milks or formulae, or animals is reflected in the circulating lipid levels of 22:6ω−3. Human milk levels of (ω − 6) and (ω − 3) fatty acids vary, depending in part on the mother's diet. A valid, scientific approach to extrapolate dietary essential fatty acid requirements from the composition of human milk or the circulating lipids of infants fed different diets has not been agreed on. Current data suggest that fatty acid requirements for development of term-gestation piglet brain and retina are met with 5.0% dietary kcal (1 cal = 4.1868 J) 18:2ω−6 and > 1.0% kcal 18:3ω−3, As in rodents and non-human primates, a diet source of 20:4ω−6 and 22:6ω−3 does not seem essential for the developing piglet central nervous system. However, studies in very premature infants suggest these infants may benefit from a dietary source of 20:4ω−6 and 22:6ω−3. Whether the low 20:4ω−6 and 22:6ω−3 status is due to oxidation of 18:2ω−6 and 18:3ω−3 for energy, the effects of early intravenous feeding with lipid emulsions, rapid growth, or immaturity of physiological or metabolic pathways in very preterm infants is not yet known.Key words: linoleic acid, linolenic acid, arachidonic acid, docosahexaenoic acid, brain, retina.
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Campos, Joana R., Patricia Severino, Classius S. Ferreira, Aleksandra Zielinska, Antonello Santini, Selma B. Souto, and Eliana B. Souto. "Linseed Essential Oil – Source of Lipids as Active Ingredients for Pharmaceuticals and Nutraceuticals." Current Medicinal Chemistry 26, no. 24 (October 11, 2019): 4537–58. http://dx.doi.org/10.2174/0929867325666181031105603.
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Linseed - also known as flaxseed - is known for its beneficial effects on animal health attributed to its composition. Linseed comprises linoleic and α-linolenic fatty acids, various dietary fibers and lignans, which are beneficial to health because they reduce the risk of cardiovascular diseases, as well as cancer, decreasing the levels of cholesterol and relaxing the smooth muscle cells in arteries increasing the blood flow. Essential fatty acids from flax participate in several metabolic processes of the cell, not only as structuring components of the cell membrane but also as storage lipids. Flax, being considered a functional food, can be consumed in a variety of ways, including seeds, oil or flour, contributing to basic nutrition. Several formulations containing flax are available on the market in the form of e.g. capsules and microencapsulated powders having potential as nutraceuticals. This paper revises the different lipid classes found in flaxseeds and their genomics. It also discusses the beneficial effects of flax and flaxseed oil and their biological advantages as ingredients in pharmaceuticals and in nutraceuticals products.
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Thompson, J. E., C. D. Froese, Y. Hong, K. A. Hudak, and M. D. Smith. "Membrane deterioration during senescence." Canadian Journal of Botany 75, no. 6 (June 1, 1997): 867–79. http://dx.doi.org/10.1139/b97-096.
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The lipid bilayers of plant membranes are normally liquid crystalline, reflecting the inherent rotational motion of membrane fatty acids at physiological temperature. With the onset of senescence, the chemical composition of membrane lipids changes resulting in lipid phase separations within the bilayer. These phase changes render the membranes leaky and lead to loss of essential ion gradients and impairment of cell function. The separation of lipid phases appears to be attributable to an accumulation of lipid metabolites in the bilayer that are formed during turnover and metabolism of membrane lipids. These metabolites are normally released from membranes as lipid–protein particles found in the cell cytosol and within organelles. The lipid–protein particles also contain catabolites of membrane proteins and appear to serve as a vehicle for removing lipid and protein metabolites that would otherwise destabilize the bilayer. They bear structural resemblance to oil bodies, which are abundant in oil seeds, and have been found in leaves, cotyledons, and petals as well as in insect and animal tissue. The accumulation of lipid metabolites in senescing membranes and ensuing separation of lipid phases appear to reflect impairment of lipid–protein particle release from membranes as tissues age and to be a seminal cause of membrane dysfunction with advancing senescence. Key words: lipid bilayer, lipid phase separation, lipid–protein particles, membrane, oil body, senescence.
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MIYAJIMA, Tohru, Takeshi TSUJINO, Komei SAITO, and Mitsuhiro YOKOYAMA. "Effects of Eicosapentaenoic Acid on Blood Pressure, Cell Membrane Fatty Acids, and Intracellular Sodium Concentration in Essential Hypertension." Hypertension Research 24, no. 5 (2001): 537–42. http://dx.doi.org/10.1291/hypres.24.537.
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Su, Chih-Chia, Philip A. Klenotic, Jani Reddy Bolla, Georgiana E. Purdy, Carol V. Robinson, and Edward W. Yu. "MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine." Proceedings of the National Academy of Sciences 116, no. 23 (May 21, 2019): 11241–46. http://dx.doi.org/10.1073/pnas.1901346116.
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The cell envelope ofMycobacterium tuberculosisis notable for the abundance of mycolic acids (MAs), essential to mycobacterial viability, and of other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, which contributes to virulence and antibiotic resistance. However, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell-wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA-containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan, but the exact function of MmpL3 remains elusive. Here, we report a crystal structure ofMycobacterium smegmatisMmpL3 at a resolution of 2.59 Å, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.
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Rajnavölgyi, Éva, Renáta Laczik, Viktor Kun, Lajos Szente, and Éva Fenyvesi. "Effects of RAMEA-complexed polyunsaturated fatty acids on the response of human dendritic cells to inflammatory signals." Beilstein Journal of Organic Chemistry 10 (December 30, 2014): 3152–60. http://dx.doi.org/10.3762/bjoc.10.332.
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The n−3 fatty acids are not produced by mammals, although they are essential for hormone synthesis and maintenance of cell membrane structure and integrity. They have recently been shown to inhibit inflammatory reactions and also emerged as potential treatment options for inflammatory diseases, such as rheumatoid arthritis, asthma and inflammatory bowel diseases. Dendritic cells (DC) play a central role in the regulation of both innate and adaptive immunity and upon inflammatory signals they produce various soluble factors among them cytokines and chemokines that act as inflammatory or regulatory mediators. In this study we monitored the effects of α-linoleic acid, eicosapentaenoic acid and docosahexaenoic acid solubilized in a dimethyl sulfoxide (DMSO)/ethanol 1:1 mixture or as complexed by randomly methylated α-cyclodextrin (RAMEA) on the inflammatory response of human monocyte-derived dendritic cells (moDC). The use of RAMEA for enhancing aqueous solubility of n−3 fatty acids has the unambiguous advantage over applying RAMEB (the β-cyclodextrin analog), since there is no interaction with cell membrane cholesterol. In vitro differentiated moDC were left untreated or were stimulated by bacterial lipopolysaccharide and polyinosinic:polycytidylic acid, mimicking bacterial and viral infections, respectively. The response of unstimulated and activated moDC to n−3 fatty acid treatment was tested by measuring the cell surface expression of CD1a used as a phenotypic and CD83 as an activation marker of inflammatory moDC differentiation and activation by using flow cytometry. Monocyte-derived DC activation was also monitored by the secretion level of the pro- and anti-inflammatory cytokines IL-1β, TNF-α, IL-6, IL-10 and IL-12, respectively. We found that RAMEA-complexed n−3 fatty acids reduced the expression of CD1a protein in both LPS and Poly(I:C) stimulated moDC significantly, but most efficiently by eicosapentaenic acid, while no significant change in the expression of CD83 protein was observed. The production of IL-6 by LPS-activated moDC was also reduced significantly when eicosapentaenic acid was added as a RAMEA complex as compared to its DMSO-solubilized form or to the other two n−3 fatty acids either complexed or not. Based on these results n−3 fatty acids solubilized by RAMEA provide with a new tool for optimizing the anti-inflammatory effects of n−3 fatty acids exerted on human moDC and mediated through the GP120 receptor without interfering with the cell membrane structure.
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agranoff, bernard. "Brain Food." Gastronomica 8, no. 3 (2008): 79–85. http://dx.doi.org/10.1525/gfc.2008.8.3.79.
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The lore and the science that recommend the eating of fish as brain food can be traced to the discovery in 1719 of a high content of phosphorus in our brains, which eventually led to the proposal of Jacob Moleschott in 1852 that there could be ““no thought without phosphorus.”” Louis Agassiz added to this the knowledge that fish, like brains, were also rich in phosphorus, and speculated that the eating of fish might improve intelligence. Mark Twain ridiculed the assertion in 1871 in a widely published humorous letter to an aspiring author that nevertheless favorably popularized the notion. We now know that the large amount phosphorus in brain is due to a high concentration of phospholipids, structural molecules of cell membranes and interconnections, such as the axons and dendrites of nerves. A dietary requirement for phosphorus was, however, not substantiated. Nutritionist's and biochemist's attention are now drawn to certain fatty acids present in phospholipids that are termed ““essential,”” meaning they cannot be biosynthesized and must therefore be derived from the diet. Eating fish and other ocean and fresh water food products is recommended based on their content of EPA and DHA, members of the omega-3 family of essential fatty acids. The omega-3 fatty acids interact with the omega-6 family of essential fatty acids, which predominate in land-based food oils. The complex interplay of the two fatty acid families relates not only to their critical presence in our cell membranes, but also in body regulatory processes via chemical messengers derivatives, the eicosanoids. An optimal ratio of our dietary intake of omega-3 to omega-6 fatty acids is deemed important for normal development of the nervous system as well as for optimizing many health-related cardiovascular and immune system functions.
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Bosson, Régine, Malika Jaquenoud, and Andreas Conzelmann. "GUP1 of Saccharomyces cerevisiae Encodes an O-Acyltransferase Involved in Remodeling of the GPI Anchor." Molecular Biology of the Cell 17, no. 6 (June 2006): 2636–45. http://dx.doi.org/10.1091/mbc.e06-02-0104.
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The anchors of mature glycosylphosphatidylinositol (GPI)-anchored proteins of Saccharomyces cerevisiae contain either ceramide or diacylglycerol with a C26:0 fatty acid in the sn2 position. The primary GPI lipid added to newly synthesized proteins in the ER consists of diacylglycerol with conventional C16 and C18 fatty acids. Here we show that GUP1 is essential for the synthesis of the C26:0-containing diacylglycerol anchors. Gup1p is an ER membrane protein with multiple membrane-spanning domains harboring a motif that is characteristic of membrane-bound O-acyl-transferases (MBOAT). Gup1Δ cells make normal amounts of GPI proteins but most mature GPI anchors contain lyso-phosphatidylinositol, and others possess phosphatidylinositol with conventional C16 and C18 fatty acids. The incorporation of the normal ceramides into the anchors is also disturbed. As a consequence, the ER-to-Golgi transport of the GPI protein Gas1p is slow, and mature Gas1p is lost from the plasma membrane into the medium. Gup1Δ cells have fragile cell walls and a defect in bipolar bud site selection. GUP1 function depends on the active site histidine of the MBOAT motif. GUP1 is highly conserved among fungi and protozoa and the gup1Δ phenotype is partially corrected by GUP1 homologues of Aspergillus fumigatus and Trypanosoma cruzi.
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Ferdous, Zannatul, Silke Fuchs, Volker Behrends, Nikolaos Trasanidis, Robert M. Waterhouse, Dina Vlachou, and George K. Christophides. "Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding." PLOS Pathogens 17, no. 5 (May 20, 2021): e1009486. http://dx.doi.org/10.1371/journal.ppat.1009486.
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Vitellogenesis and oocyte maturation require anautogenous female Anopheles mosquitoes to obtain a bloodmeal from a vertebrate host. The bloodmeal is rich in proteins that are readily broken down into amino acids in the midgut lumen and absorbed by the midgut epithelial cells where they are converted into lipids and then transported to other tissues including ovaries. The stearoyl-CoA desaturase (SCD) plays a pivotal role in this process by converting saturated (SFAs) to unsaturated (UFAs) fatty acids; the latter being essential for maintaining cell membrane fluidity amongst other housekeeping functions. Here, we report the functional and phenotypic characterization of SCD1 in the malaria vector mosquito Anopheles coluzzii. We show that RNA interference (RNAi) silencing of SCD1 and administration of sterculic acid (SA), a small molecule inhibitor of SCD1, significantly impact on the survival and reproduction of female mosquitoes following blood feeding. Microscopic observations reveal that the mosquito thorax is quickly filled with blood, a phenomenon likely caused by the collapse of midgut epithelial cell membranes, and that epithelial cells are depleted of lipid droplets and oocytes fail to mature. Transcriptional profiling shows that genes involved in protein, lipid and carbohydrate metabolism and immunity-related genes are the most affected by SCD1 knock down (KD) in blood-fed mosquitoes. Metabolic profiling reveals that these mosquitoes exhibit increased amounts of saturated fatty acids and TCA cycle intermediates, highlighting the biochemical framework by which the SCD1 KD phenotype manifests as a result of a detrimental metabolic syndrome. Accumulation of SFAs is also the likely cause of the potent immune response observed in the absence of infection, which resembles an auto-inflammatory condition. These data provide insights into mosquito bloodmeal metabolism and lipid homeostasis and could inform efforts to develop novel interventions against mosquito-borne diseases.
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Thomson, A. B. R., C. Schoeller, M. Keelan, L. Smith, and M. T. Clandinin. "Lipid absorptions passing through the unstirred layers, brush-border membrane, and beyond." Canadian Journal of Physiology and Pharmacology 71, no. 8 (August 1, 1993): 531–55. http://dx.doi.org/10.1139/y93-078.
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Lipids are components of our diet and luminal secretions, with physicochemical characteristics that determine their digestion and absorption in the gastrointestinal tract. Lipids include triglycerides, phospholipids, and cholesterol. Dietary lipids contain approximately 97% triglycerides, with small amounts of phospholipids and cholesterol. These components are important in cell membrane composition, fluidity, peroxidation, prostaglandin and leukotriene synthesis, and cellular metabolic processes. Lipids are implicated in the mechanisms of brain development, inflammatory processes, atherosclerosis, carcinogenesis, aging, and cell renewal. Duodenal hydrolysis of dietary lipids and biliary phospholipids and cholesterol is carried out by pancreatic lipase, colipase, phospholipase A2, and cholesterol esterase. Bile acid solubilization results in mixed micelles and liposomes, in gel and liquid crystal phases. Lipid digestion products pass across the intestinal unstirred water layer. For long-chain fatty acids and cholesterol, passage across the unstirred water layer is rate limiting, whereas passage of short- and medium-chain fatty acids is limited by the brush-border membrane. Within the unstirred water layer, an acidic microclimate aids micellar dissociation so that protonated, and to a lesser extent, nonprotonated monomers then pass across the intestinal brush-border membrane. Absorptive mechanisms have been studied extensively in relation to lipid composition, fatty acid chain length, degree of unsaturation, essential fatty acid content, phospholipid components, and cholesterol. Enterocytes may take up lipids from the intestinal lumen or from lipoproteins of the bloodstream, but these pools are likely to be functionally distinct. Recent advances are reviewed, including recent advances in the area of microclimates, compartmentation, lipid binding proteins, intracellular trafficking, intestinal lipoproteins, release of lipids across the basolateral membrane, and dietary effects.Key words: diet effects, lipid binding proteins, lipoproteins.
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Warren, G., M. McKendrick, and M. Pea. "The role of essential fatty acids in chronic fatigue syndrome: A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA." Acta Neurologica Scandinavica 99, no. 2 (February 1999): 112–16. http://dx.doi.org/10.1111/j.1600-0404.1999.tb00667.x.
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Kurth, Daniel G., Gabriela M. Gago, Agustina de la Iglesia, Bernardo Bazet Lyonnet, Ting-Wan Lin, Héctor R. Morbidoni, Shiou-Chuan Tsai, and Hugo Gramajo. "ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria." Microbiology 155, no. 8 (August 1, 2009): 2664–75. http://dx.doi.org/10.1099/mic.0.027714-0.
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Mycolic acids are essential for the survival, virulence and antibiotic resistance of the human pathogen Mycobacterium tuberculosis. Inhibitors of mycolic acid biosynthesis, such as isoniazid and ethionamide, have been used as efficient drugs for the treatment of tuberculosis. However, the increase in cases of multidrug-resistant tuberculosis has prompted a search for new targets and agents that could also affect synthesis of mycolic acids. In mycobacteria, the acyl-CoA carboxylases (ACCases) provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase (FAS) I and for the elongation of FAS I products by the FAS II complex to produce meromycolic acids. By generating a conditional mutant in the accD6 gene of Mycobacterium smegmatis, we demonstrated that AccD6 is the essential carboxyltransferase component of the ACCase 6 enzyme complex implicated in the biosynthesis of malonyl-CoA, the substrate of the two FAS enzymes of Mycobacterium species. Based on the conserved structure of the AccD5 and AccD6 active sites we screened several inhibitors of AccD5 as potential inhibitors of AccD6 and found that the ligand NCI-172033 was capable of inhibiting AccD6 with an IC50 of 8 μM. The compound showed bactericidal activity against several pathogenic Mycobacterium species by producing a strong inhibition of both fatty acid and mycolic acid biosynthesis at minimal inhibitory concentrations. Overexpression of accD6 in M. smegmatis conferred resistance to NCI-172033, confirming AccD6 as the main target of the inhibitor. These results define the biological role of a key ACCase in the biosynthesis of membrane and cell envelope fatty acids, and provide a new target, AccD6, for rational development of novel anti-mycobacterial drugs.
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Koundouros, Nikos, and George Poulogiannis. "Reprogramming of fatty acid metabolism in cancer." British Journal of Cancer 122, no. 1 (December 10, 2019): 4–22. http://dx.doi.org/10.1038/s41416-019-0650-z.
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AbstractA common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
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Cerrato, S., L. Ramió-Lluch, D. Fondevila, D. Rodes, P. Brazis, and A. Puigdemont. "Effects of Essential Oils and Polyunsaturated Fatty Acids on Canine Skin Equivalents: Skin Lipid Assessment and Morphological Evaluation." Journal of Veterinary Medicine 2013 (November 6, 2013): 1–9. http://dx.doi.org/10.1155/2013/231526.
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A canine skin equivalent model has been validated for the assessment of a topical formulation effects. Skin equivalents were developed from freshly isolated cutaneous canine fibroblasts and keratinocytes, after enzymatic digestion of skin samples (n=8) from different breeds. Fibroblasts were embedded into a collagen type I matrix, and keratinocytes were seeded onto its surface at air-liquid interface. Skin equivalents were supplemented with essential oils and polyunsaturated fatty acid formulation or with vehicle. Skin equivalents were histopathologically and ultrastructurally studied, and the three main lipid groups (free fatty acids, cholesterol, and ceramides) were analyzed. Results showed that the culture method developed resulted in significant improvements in cell retrieval and confluence. Treated samples presented a thicker epidermis with increased number of viable cell layers, a denser and compact stratum corneum, and a more continuous basal membrane. Regarding lipid profile, treated skin equivalents showed a significant increase in ceramide content (51.7±1.3) when compared to untreated (41.6 ± 1.4) samples. Ultrastructural study evidenced a compact and well-organized stratum corneum in both treated and control skin equivalents. In conclusion, cell viability and ceramides increase, after lipid supplementation, are especially relevant for the treatment of skin barrier disruptions occurring in canine atopic dermatitis.
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Okpala, Iheanyi, Hongmei Ren, Obike Ibegbulam, Cynthia C. Ugochukwu, Kebreab Ghebremeskel, and Michael Crawford. "Steady State Haemoglobin Level Increases with the Proportion of Erythrocyte Membrane n-3 Fatty Acids in Sickle Cell Anaemia." Blood 104, no. 11 (November 16, 2004): 3566. http://dx.doi.org/10.1182/blood.v104.11.3566.3566.
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Abstract Previous studies indicate that perturbation of erythrocyte and/or plasma lipids occurs in homozygous sickle cell disease (SCD), and treatment with n-3 fatty acids (FA) is beneficial to affected individuals (Tomer et al, Thromb Haemost2001; 966–974). Phosphatidylserine has a role in sickle erythrocyte-endothelial adhesion, which contributes to vessel occlusion in SCD (Setty et al, Blood2002; 1564–1571). Considering that n-3 and n-6 FA are essential structural and functional components of the red cell membrane, the objective of this study was to find out if abnormalities of these FA affect the degree of anaemia in SCD. We recruited 43 HbSS patients and 43 racially-matched, healthy, HbAA controls living in the same environment; analysed the fatty acid composition of erythrocyte membrane choline (CPG), serine (SPG) and ethanolamine (EPG) phosphoglycerides and sphingomyelin (SPM); and sought for relationship between steady-state Hb level in SCD and the proportion of n-3 FA in the red cell membrane. HbSS individuals had high levels of adrenic and docosapentanoic acids in CPG, EPG, SPG (p<0.001), and SPM (p<0.05). Arachidonic acid (AA) was increased in CPG (p<0.001) and EPG (p<0.005) of the patients. In contrast, linoleic acid (LA) was low in patients’ CPG, EPG, SPG and SPM (p<0.001). Both LA and AA were reduced in plasma CPG, triglycerides and cholesterol esters of SCD patients. There was significant positive correlation between steady-state Hb level and n-3 FA content of erythrocytes: docosahexaenoic (DHA, p<0.01, r = 0.63) and eicosapentanoic (EPA) acids in red cell CPG, and EPA in EPG (p<0.05, r = 0.60); figs. 1&2. The observed high AA with low DHA/EPA levels favour red cell adherence to vascular endothelium and vaso-occlusion. The data suggest that in SCD: synthesis of AA and/or membrane uptake of LA and AA may be abnormal; increased proportions of erythrocyte membrane DHA and EPA confer some resistance to haemolysis.
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Ballweg, Stephanie, and Robert Ernst. "Control of membrane fluidity: the OLE pathway in focus." Biological Chemistry 398, no. 2 (February 1, 2017): 215–28. http://dx.doi.org/10.1515/hsz-2016-0277.
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Abstract The maintenance of a fluid lipid bilayer is key for membrane integrity and cell viability. We are only beginning to understand how eukaryotic cells sense and maintain the characteristic lipid compositions and bulk membrane properties of their organelles. One of the key factors determining membrane fluidity and phase behavior is the proportion of saturated and unsaturated acyl chains in membrane lipids. Saccharomyces cerevisiae is an ideal model organism to study the regulation of the lipid acyl chain composition via the OLE pathway. The OLE pathway comprises all steps involved in the regulated mobilization of the transcription factors Mga2 and Spt23 from the endoplasmic reticulum (ER), which then drive the expression of OLE1 in the nucleus. OLE1 encodes for the essential Δ9-fatty acid desaturase Ole1 and is crucial for de novo biosynthesis of unsaturated fatty acids (UFAs) that are used as lipid building blocks. This review summarizes our current knowledge of the OLE pathway, the best-characterized, eukaryotic sense-and-control system regulating membrane lipid saturation, and identifies open questions to indicate future directions.
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To, Thi Mai Huong, Cosette Grandvalet, and Raphaëlle Tourdot-Maréchal. "Cyclopropanation of Membrane Unsaturated Fatty Acids Is Not Essential to the Acid Stress Response of Lactococcus lactis subsp. cremoris." Applied and Environmental Microbiology 77, no. 10 (March 18, 2011): 3327–34. http://dx.doi.org/10.1128/aem.02518-10.
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ABSTRACTCyclopropane fatty acids (CFAs) are synthetizedin situby the transfer of a methylene group fromS-adenosyl-l-methionine to a double bond of unsaturated fatty acid chains of membrane phospholipids. This conversion, catalyzed by the Cfa synthase enzyme, occurs in many bacteria and is recognized to play a key role in the adaptation of bacteria in response to a drastic perturbation of the environment. The role of CFAs in the acid tolerance response was investigated in the lactic acid bacteriumLactococcus lactisMG1363. A mutant of thecfagene was constructed by allelic exchange. Thecfagene encoding the Cfa synthase was cloned and introduced into the mutant to obtain the complemented strain for homologous system studies. Data obtained by gas chromatography (GC) and GC-mass spectrometry (GC-MS) validated that the mutant could not produce CFA. The CFA levels in both the wild-type and complemented strains increased upon their entry to stationary phase, especially with acid-adapted cells or, more surprisingly, with ethanol-adapted cells. The results obtained by performing quantitative reverse transcription-PCR (qRT-PCR) experiments showed that transcription of thecfagene was highly induced by acidity (by 10-fold with cells grown at pH 5.0) and by ethanol (by 9-fold with cells grown with 6% ethanol) in comparison with that in stationary phase. Cell viability experiments were performed after an acidic shock on the mutant strain, the wild-type strain, and the complemented strain, as a control. The higher viability level of the acid-adapted cells of the three strains after 3 h of shock proved that the cyclopropanation of unsaturated fatty acids is not essential forL. lactissubsp.cremorissurvival under acidic conditions. Moreover, fluorescence anisotropy data showed that CFA itself could not maintain the membrane fluidity level, particularly with ethanol-grown cells.
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Soupene, Eric, Melvin Siliakus, and Frans A. Kuypers. "Acyl-CoA Turnover in RBC." Blood 108, no. 11 (November 16, 2006): 1579. http://dx.doi.org/10.1182/blood.v108.11.1579.1579.
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Abstract The formation, distribution and utilization of acyl-CoA plays a crucial role in plasma membrane phospholipid turnover in red blood cells (RBC). Upon de-acylation of glycero-phospholipids (PL) via the action of phospholipase, re-acylation of the lysophospholipids (LPL) requires activity of two enzymes of the Lands pathway. Long-chain acyl-CoA synthetases (ACSL) activate fatty acids to acyl-CoA which are subsequently ligated to LPL by LysoPhosphoLipid Acyl Transferase (LPLAT) a family of enzymes with exclusive specificity for the polar group of LPL (phosphatidic acid, choline, serine and ethanolamine). While formation and utilization of acyl-CoA takes place at the membrane, Acyl-CoA Binding Domain containing proteins (ACBD) in RBC cytosol bind acyl-CoA, limiting product feedback inhibition on ACSL and distribute Acyl-CoA to the various acyl-utilizing enzymes while protecting the cells against its potent detergent character. We have identified ACSL6 as the enzyme responsible for the activation of fatty acid in RBC, a protein with several isoforms that acts as a dimer. To relate its structure to activity, we report the expression of different modified forms in E. coli. Our data indicate that, despite the observed activity, enzyme studies of these mammalian membrane proteins in the host E. coli are strongly hampered by their aggregation into inclusion bodies. While activity can be measured, data on enzyme kinetics and specificity are questionable. Oleoyl-CoA formation from oleic acid, CoA and ATP reveled that the two transmembrane spanning segments predicted at the amino-terminus of the protein are not essential for its activity. Moreover, they are not essential for dimer formation and strong association with membranes. ACSL6 appears to be an integral membrane protein. One of the five spliced isoforms of ACSL6 reported, lacks the so-called fatty acid Gate-domain, and appears to be unable to activate long chain fatty acids. We hypothesize that this form modulates activity of the other active isoforms of ACSL6 through hetero-dimer formation. An EST clone of erythroid precursor cells identified ACBD6 as a potential AcylCoA binding protein in RBC. This modular protein contains an Acyl-CoA binding domain at the amino-terminus and two Ankyrin-repeat motifs (ANK) at the C-terminus. Both the full-length protein and the N-terminus domain were soluble when expressed and purified in E. coli. Expression of the C-terminus domain by itself rendered an insoluble protein. We report that ACBD6 binds long-chain acyl-CoA with a preference for C18:1-CoA over C20:4 and C16:0-CoA and does not bind fatty acid. Truncation of the ANK domain had no effect on the binding activity of the N-terminus domain. Together our findings implicate ACBD6 as part of the Acyl-CoA turnover mechanism in RBC, its actual role on the kinetics of ACSL and/or LPLAT activity needs to be established. The description of these proteins involved in Acyl-CoA turnover in RBC will aid to better understand the maintenance of plasma membrane lipid composition of all mammalian cells.
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Shigetomi, Kenta, Yumiko Ono, Tetsuichiro Inai, and Junichi Ikenouchi. "Adherens junctions influence tight junction formation via changes in membrane lipid composition." Journal of Cell Biology 217, no. 7 (May 2, 2018): 2373–81. http://dx.doi.org/10.1083/jcb.201711042.
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Tight junctions (TJs) are essential cell adhesion structures that act as a barrier to separate the internal milieu from the external environment in multicellular organisms. Although their major constituents have been identified, it is unknown how the formation of TJs is regulated. TJ formation depends on the preceding formation of adherens junctions (AJs) in epithelial cells; however, the underlying mechanism remains to be elucidated. In this study, loss of AJs in α-catenin–knockout (KO) EpH4 epithelial cells altered the lipid composition of the plasma membrane (PM) and led to endocytosis of claudins, a major component of TJs. Sphingomyelin with long-chain fatty acids and cholesterol were enriched in the TJ-containing PM fraction. Depletion of cholesterol abolished the formation of TJs. Conversely, addition of cholesterol restored TJ formation in α-catenin–KO cells. Collectively, we propose that AJs mediate the formation of TJs by increasing the level of cholesterol in the PM.
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Lauridsen, Charlotte. "54 Lipid nutrition and gut health of pigs." Journal of Animal Science 97, Supplement_2 (July 2019): 28. http://dx.doi.org/10.1093/jas/skz122.051.
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Abstract Lipids and fatty acids play major roles in relation to mucosal immune responses, epithelial barrier functions, oxidative stress and inflammatory reactions. The composition of fatty acids and their molecular structures (chain length and number of double bonds) influences digestion, absorption and metabolism of the dietary fat, as well as the bioactivity of the fatty acids. Piglets post weaning having immature intestines and immune functions are very vulnerable towards invading microorganisms. Manipulation of the milk fatty acid composition via the sow nutrition, or inclusion of dietary fat sources in the feed, may be used as a strategic tool to enhance pig performance and their gut health pre- and post weaning. Medium-chained fatty acids (MCFA) are absorbed directly into the portal blood and may contribute with immediate energy for the piglet. In addition, the MCFA possess antibacterial effects. The essential fatty acids, linoleic and linolenic fatty acids, form the building blocks for the longer –chained polyunsaturated n-3 and n-6 fatty acids. Their conversion into n-3 and n-6 eicosanoids influence the inflammatory reactions and the immune responses upon bacterial challenge. The proportion of unsaturated fatty acids in the cell membranes influence the susceptibility to oxidative stress. Oxidative stress accompanies infectious diseases, and if uncontrolled, the development of the lipid peroxides may be harmful for the epithelial barrier function. The aim of this presentation is to review how dietary fatty acid composition during critical phases of pigs’ lives can support a normal immune system and modulate resistance to infectious diseases of pigs, and influence growth of the pig. Furthermore, factors that can enhance oxidative stress (e.g. polyunsaturated fatty acids), uncontrolled inflammatory reactions (e.g. high ratio of n-6 to n-3 fatty acids in cellular membranes), and limit immune development (such as deficiency of fat-soluble vitamins), and be harmful for the pig gut health are addressed.
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Lezo, Antonella, Valentina D’Onofrio, Maria Paola Puccinelli, Teresa Capriati, Antonella De Francesco, Simona Bo, Paola Massarenti, et al. "Plasma and Red Blood Cell PUFAs in Home Parenteral Nutrition Paediatric Patients—Effects of Lipid Emulsions." Nutrients 12, no. 12 (December 5, 2020): 3748. http://dx.doi.org/10.3390/nu12123748.
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Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9–21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth.
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Steinhauer, Josefa, Miguel A. Gijón, Wayne R. Riekhof, Dennis R. Voelker, Robert C. Murphy, and Jessica E. Treisman. "Drosophila Lysophospholipid Acyltransferases Are Specifically Required for Germ Cell Development." Molecular Biology of the Cell 20, no. 24 (December 15, 2009): 5224–35. http://dx.doi.org/10.1091/mbc.e09-05-0382.
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Enzymes of the membrane-bound O-acyltransferase (MBOAT) family add fatty acyl chains to a diverse range of protein and lipid substrates. A chromosomal translocation disrupting human MBOAT1 results in a novel syndrome characterized by male sterility and brachydactyly. We have found that the Drosophila homologues of MBOAT1, Oysgedart (Oys), Nessy (Nes), and Farjavit (Frj), are lysophospholipid acyltransferases. When expressed in yeast, these MBOATs esterify specific lysophospholipids preferentially with unsaturated fatty acids. Generating null mutations for each gene allowed us to identify redundant functions for Oys and Nes in two distinct aspects of Drosophila germ cell development. Embryos lacking both oys and nes show defects in the ability of germ cells to migrate into the mesoderm, a process guided by lipid signals. In addition, oys nes double mutant adult males are sterile due to specific defects in spermatid individualization. oys nes mutant testes, as well as single, double, and triple mutant whole adult animals, show an increase in the saturated fatty acid content of several phospholipid species. Our findings suggest that lysophospholipid acyltransferase activity is essential for germline development and could provide a mechanistic explanation for the etiology of the human MBOAT1 mutation.
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Abel, S., S. Riedel, and W. C. A. Gelderblom. "Dietary PUFA and cancer." Proceedings of the Nutrition Society 73, no. 3 (May 22, 2014): 361–67. http://dx.doi.org/10.1017/s0029665114000585.
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The aim of the present paper is to give a brief overview on the role of dietary fat in carcinogenesis and as possible anticancer agents. Dietary fat is an essential nutrient and important source for the essential fatty acids (FA), linoleic and α-linolenic acids, which contribute to proper growth and development. However, dietary fat has been associated with the development of colorectal, breast, prostate, endometrial and ovarian cancers, with the type and quality of fat playing an underlying role. Tumour growth is the disruption of the homoeostatic balance regulating cell differentiation, proliferation and apoptosis and is associated with altered lipid metabolism. Animal cancer models and human cancer biopsy tissue demonstrate that a characteristic lipid profile is associated with the growth and development of neoplastic lesions. This entails alterations in membrane cholesterol, phospholipid and PUFA metabolism. Particularly, alterations in cell membrane FA metabolism involving the n-6 and n-3 PUFA, are associated with changes in membrane structure, function, cellular oxidative status, activity of enzymes and signalling pathways. These events are a driving force in sustaining the altered growth of cancerous lesions and provide unique targets for intervention/cancer modulation. Challenges in utilising FA in cancer modulation exist regarding intake and effect on cell structure and biochemical interactions within the cell in the prevention of cancer development. Therefore, utilising dietary PUFA in a specific n-6:n-3 ratio may be an important chemopreventive tool in altering the growth characteristics of cancer cells.
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Wojdasiewicz, Piotr, Łukasz A. Poniatowski, Paweł Turczyn, Justyna Frasuńska, Agnieszka Paradowska-Gorycka, and Beata Tarnacka. "Significance of Omega-3 Fatty Acids in the Prophylaxis and Treatment after Spinal Cord Injury in Rodent Models." Mediators of Inflammation 2020 (July 29, 2020): 1–11. http://dx.doi.org/10.1155/2020/3164260.
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Polyunsaturated fatty acids (ω-3 acids, PUFAs) are essential components of cell membranes in all mammals. A multifactorial beneficial influence of ω-3 fatty acids on the health of humans and other mammals has been observed for many years. Therefore, ω-3 fatty acids and their function in the prophylaxis and treatment of various pathologies have been subjected to numerous studies. Regarding the documented therapeutic influence of ω-3 fatty acids on the nervous and immune systems, the aim of this paper is to present the current state of knowledge and the critical assessment of the role of ω-3 fatty acids in the prophylaxis and treatment of spinal cord injury (SCI) in rodent models. The prophylactic properties (pre-SCI) include the stabilization of neuron cell membranes, the reduction of the expression of inflammatory cytokines (IL-1β, TNF-α, IL-6, and KC/GRO/CINC), the improvement of local blood flow, reduced eicosanoid production, activation of protective intracellular transcription pathways (dependent on RXR, PPAR-α, Akt, and CREB), and increased concentration of lipids, glycogen, and oligosaccharides by neurons. On the other hand, the therapeutic properties (post-SCI) include the increased production of endogenous antioxidants such as carnosine and homocarnosine, the maintenance of elevated GSH concentrations at the site of injury, reduced concentrations of oxidative stress marker (MDA), autophagy improvement (via increasing the expression of LC3-II), and p38 MAPK expression reduction in the superficial dorsal horns (limiting the sensation of neuropathic pain). Paradoxically, despite the well-documented protective activity of ω-3 acids in rodents with SCI, the research does not offer an answer to the principal question of the optimal dose and treatment duration. Therefore, it is worth emphasizing the role of multicenter rodent studies with the implementation of standards which initially may even be based on arbitrary criteria. Additionally, basing on available research data, the authors of this paper make a careful attempt at referring some of the conclusions to the human population.
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Pironi, Loris, Andrea Belluzzi, and Mario Miglioli. "Low Levels of Essential Fatty Acids in the Red Blood Cell Membrane Phospholipid Fraction of Long-Term Home Parenteral Nutrition Patients." Journal of Parenteral and Enteral Nutrition 20, no. 5 (September 1996): 377–78. http://dx.doi.org/10.1177/0148607196020005377.
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