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Zhou, Jie, Marcia R. Terluk, Paul J. Orchard, James C. Cloyd e Reena V. Kartha. "N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy". Biomedicines 9, n.º 12 (3 de dezembro de 2021): 1826. http://dx.doi.org/10.3390/biomedicines9121826.
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The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1–100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.
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McGuinness, M. C., J. F. Lu, H. P. Zhang, G. X. Dong, A. K. Heinzer, P. A. Watkins, J. Powers e K. D. Smith. "Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy". Molecular and Cellular Biology 23, n.º 2 (15 de janeiro de 2003): 744–53. http://dx.doi.org/10.1128/mcb.23.2.744-753.2003.
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ABSTRACT Peroxisomal disorders have been associated with malfunction of peroxisomal metabolic pathways, but the pathogenesis of these disorders is largely unknown. X-linked adrenoleukodystrophy (X-ALD) is associated with elevated levels of very-long-chain fatty acids (VLCFA; C>22:0) that have been attributed to reduced peroxisomal VLCFA β-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA β-oxidation in human and mouse X-ALD fibroblasts. In this study, we found normal levels of peroxisomal VLCFA β-oxidation in tissues from ALD mice with elevated VLCFA levels. Treatment of ALD mice with pharmacological agents resulted in decreased VLCFA levels without a change in VLCFA β-oxidation activity. These data indicate that ALDP does not determine the rate of VLCFA β-oxidation and that VLCFA levels are not determined by the rate of VLCFA β-oxidation. The rate of peroxisomal VLCFA β-oxidation in human and mouse fibroblasts in vitro is affected by the rate of mitochondrial long-chain fatty acid β-oxidation. We hypothesize that ALDP facilitates the interaction between peroxisomes and mitochondria, resulting, when ALDP is deficient in X-ALD, in increased VLCFA accumulation despite normal peroxisomal VLCFA β-oxidation in ALD mouse tissues. In support of this hypothesis, mitochondrial structural abnormalities were observed in adrenal cortical cells of ALD mice.
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Siigur, Jüri, Katrin Trummal, Külli TÕnismägi, Mari Samel, Ene Siigur, Heikki Vija, Indrek Tammiste e Juhan Subbi. "Use of MALDI-TOF Mass Spectrometry for Specificity Studies of Biomedically Important Proteases". Spectroscopy 16, n.º 3-4 (2002): 161–70. http://dx.doi.org/10.1155/2002/204307.
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Proteases play crucial role starting from fertilization until to cell death. Our studies of the two Viperidae venoms (Levantine viperVipera lebetina, Common viperVipera berus) have demonstrated the existence of biomedically important proteases, both coagulants and anticoagulants that may be useful as diagnostic tools or potential therapeutics. We showed that venoms of both snakes contain: (i) metalloproteases and serine proteases that degrade fibrinogen, but not fibrin; (ii) factor X activators (VLFXA, VBFXAE); (iii) bradykinin-releasing serine proteases. AdditionallyVipera lebetinasnake venom contains thrombolytic fibrin degrading metalloenzyme (lebetase), HUVEC cell apoptosis inducing metalloprotease (VLAIP), factor V activator (VLFVA), thermostable β-fibrinogenase and α-fibrinogenase which has no homolog among known serine proteases. We examined the activity of snake venom proteases against bradykinin, substance P, insulin B-chain and 6–10 amino acid residues containing peptides synthesized according to potential cleavage regions of fibrinogen, factor X, factor IX, factor V, α2-macroglobulin bait region and pregnancy zone protein (PZP). We used MALDI TOF mass spectrometry technique for the discovery and identification of peptides released by protease hydrolysis. The sensitive and quick MALDI-TOF mass spectrometry methodology allows us to obtain the primary information about the substrate specificity of different proteases against various peptides and proteins.
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Batsale, Marguerite, Delphine Bahammou, Laetitia Fouillen, Sébastien Mongrand, Jérôme Joubès e Frédéric Domergue. "Biosynthesis and Functions of Very-Long-Chain Fatty Acids in the Responses of Plants to Abiotic and Biotic Stresses". Cells 10, n.º 6 (21 de maio de 2021): 1284. http://dx.doi.org/10.3390/cells10061284.
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Very-long-chain fatty acids (i.e., fatty acids with more than 18 carbon atoms; VLCFA) are important molecules that play crucial physiological and structural roles in plants. VLCFA are specifically present in several membrane lipids and essential for membrane homeostasis. Their specific accumulation in the sphingolipids of the plasma membrane outer leaflet is of primordial importance for its correct functioning in intercellular communication. VLCFA are found in phospholipids, notably in phosphatidylserine and phosphatidylethanolamine, where they could play a role in membrane domain organization and interleaflet coupling. In epidermal cells, VLCFA are precursors of the cuticular waxes of the plant cuticle, which are of primary importance for many interactions of the plant with its surrounding environment. VLCFA are also major components of the root suberin barrier, which has been shown to be fundamental for nutrient homeostasis and plant adaptation to adverse conditions. Finally, some plants store VLCFA in the triacylglycerols of their seeds so that they later play a pivotal role in seed germination. In this review, taking advantage of the many studies conducted using Arabidopsis thaliana as a model, we present our current knowledge on the biosynthesis and regulation of VLCFA in plants, and on the various functions that VLCFA and their derivatives play in the interactions of plants with their abiotic and biotic environment.
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Zhukov, Anatoly, e Valery Popov. "Synthesis of C20–38 Fatty Acids in Plant Tissues". International Journal of Molecular Sciences 23, n.º 9 (25 de abril de 2022): 4731. http://dx.doi.org/10.3390/ijms23094731.
Texto completo da fonteResumo:
Very-long-chain fatty acids (VLCFA) are involved in a number of important plant physiological functions. Disorders in the expression of genes involved in the synthesis of VLCFA lead to a number of phenotypic consequences, ranging from growth retardation to the death of embryos. The elongation of VLCFA in the endoplasmic reticulum (ER) is carried out by multiple elongase complexes with different substrate specificities and adapted to the synthesis of a number of products required for a number of metabolic pathways. The information about the enzymes involved in the synthesis of VLCFA with more than 26 atoms of Carbon is rather poor. Recently, genes encoding enzymes involved in the synthesis of both regular-length fatty acids and VLCFA have been discovered and investigated. Polyunsaturated VLCFA in plants are formed mainly by 20:1 elongation into new monounsaturated acids, which are then imported into chloroplasts, where they are further desaturated. The formation of saturated VLCFA and their further transformation into a number of aliphatic compounds included in cuticular waxes and suberin require the coordinated activity of a large number of different enzymes.
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Zhukov, Anatoly, e Valery Popov. "Synthesis of C20–38 Fatty Acids in Plant Tissues". International Journal of Molecular Sciences 23, n.º 9 (25 de abril de 2022): 4731. http://dx.doi.org/10.3390/ijms23094731.
Texto completo da fonteResumo:
Very-long-chain fatty acids (VLCFA) are involved in a number of important plant physiological functions. Disorders in the expression of genes involved in the synthesis of VLCFA lead to a number of phenotypic consequences, ranging from growth retardation to the death of embryos. The elongation of VLCFA in the endoplasmic reticulum (ER) is carried out by multiple elongase complexes with different substrate specificities and adapted to the synthesis of a number of products required for a number of metabolic pathways. The information about the enzymes involved in the synthesis of VLCFA with more than 26 atoms of Carbon is rather poor. Recently, genes encoding enzymes involved in the synthesis of both regular-length fatty acids and VLCFA have been discovered and investigated. Polyunsaturated VLCFA in plants are formed mainly by 20:1 elongation into new monounsaturated acids, which are then imported into chloroplasts, where they are further desaturated. The formation of saturated VLCFA and their further transformation into a number of aliphatic compounds included in cuticular waxes and suberin require the coordinated activity of a large number of different enzymes.
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Bourassa, Dianna V., Elmar L. Kannenberg, D. Janine Sherrier, R. Jeffrey Buhr e Russell W. Carlson. "The Lipopolysaccharide Lipid A Long-Chain Fatty Acid Is Important for Rhizobium leguminosarum Growth and Stress Adaptation in Free-Living and Nodule Environments". Molecular Plant-Microbe Interactions® 30, n.º 2 (fevereiro de 2017): 161–75. http://dx.doi.org/10.1094/mpmi-11-16-0230-r.
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Rhizobium bacteria live in soil and plant environments, are capable of inducing symbiotic nodules on legumes, invade these nodules, and develop into bacteroids that fix atmospheric nitrogen into ammonia. Rhizobial lipopolysaccharide (LPS) is anchored in the bacterial outer membrane through a specialized lipid A containing a very long-chain fatty acid (VLCFA). VLCFA function for rhizobial growth in soil and plant environments is not well understood. Two genes, acpXL and lpxXL, encoding acyl carrier protein and acyltransferase, are among the six genes required for biosynthesis and transfer of VLCFA to lipid A. Rhizobium leguminosarum mutant strains acpXL, acpXL−/lpxXL−, and lpxXL− were examined for LPS structure, viability, and symbiosis. Mutations in acpXL and lpxXL abolished VLCFA attachment to lipid A. The acpXL mutant transferred a shorter acyl chain instead of VLCFA. Strains without lpxXL neither added VLCFA nor a shorter acyl chain. In all strains isolated from nodule bacteria, lipid A had longer acyl chains compared with laboratory-cultured bacteria, whereas mutant strains displayed altered membrane properties, modified cationic peptide sensitivity, and diminished levels of cyclic β-glucans. In pea nodules, mutant bacteroids were atypically formed and nitrogen fixation and senescence were affected. The role of VLCFA for rhizobial environmental fitness is discussed.
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Robinson, B. S., D. W. Johnson e A. Poulos. "Unique molecular species of phosphatidylcholine containing very-long-chain (C24-C38) polyenoic fatty acids in rat brain". Biochemical Journal 265, n.º 3 (1 de fevereiro de 1990): 763–67. http://dx.doi.org/10.1042/bj2650763.
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Rat brain has been shown to contain polyenoic very-long-chain fatty acids (VLCFA) belonging to the n-3 and n-6 series with four, five and six double bonds and even-carbon chain lengths from 24 to 38. These fatty acids are almost exclusively located in unusual molecular species of phosphatidylcholine at the sn-1 position of the glycerol backbone, whereas saturated, monoenoic and polyenoic fatty acids with less than 24 carbon atoms are present at the sn-2 position. Polyenoic VLCFA phosphatidylcholine in neonatal rat brain is enriched with n-6 pentaenoic and n-3 hexaenoic VLCFA with up to 36 carbon atoms, whereas the corresponding phospholipid in adult rat brain mainly contains n-6 tetraenoic and n-3 pentaenoic VLCFA with up to 38 carbon atoms. The total amount of polyenoic VLCFA associated with phosphatidylcholine is highest in the brain of immature animals. Polyenoic VLCFA phosphatidylcholine appears to be predominantly confined to nervous tissue in rats, and it is envisaged that this phospholipid is of physiological significance.
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Trinh, Duy-Chi, Julien Lavenus, Tatsuaki Goh, Yohann Boutté, Quentin Drogue, Virginie Vaissayre, Frédérique Tellier et al. "PUCHI regulates very long chain fatty acid biosynthesis during lateral root and callus formation". Proceedings of the National Academy of Sciences 116, n.º 28 (24 de junho de 2019): 14325–30. http://dx.doi.org/10.1073/pnas.1906300116.
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Lateral root organogenesis plays an essential role in elaborating plant root system architecture. InArabidopsis, the AP2 family transcription factor PUCHI controls cell proliferation in lateral root primordia. To identify potential targets of PUCHI, we analyzed a time course transcriptomic dataset of lateral root formation. We report that multiple genes coding for very long chain fatty acid (VLCFA) biosynthesis enzymes are induced during lateral root development in a PUCHI-dependent manner. Significantly, several mutants perturbed in VLCFA biosynthesis show similar lateral root developmental defects aspuchi-1. Moreover,puchi-1roots display the same disorganized callus formation phenotype as VLCFA biosynthesis-deficient mutants when grown on auxin-rich callus-inducing medium. Lipidomic profiling ofpuchi-1roots revealed reduced VLCFA content compared with WT. We conclude that PUCHI-regulated VLCFA biosynthesis is part of a pathway controlling cell proliferation during lateral root and callus formation.
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Williams, John, Kan Zhu, Eric Crampon e André Iffland. "Fit-for-purpose biomarker LC–MS/MS qualification for the quantitation of very long chain fatty acids in human cerebrospinal fluid". Bioanalysis 12, n.º 3 (fevereiro de 2020): 143–58. http://dx.doi.org/10.4155/bio-2019-0256.
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Aim: Very long chain fatty acids (VLCFAs) have been identified as biomarkers for several peroxisomal disorders necessitating the need for reliable biomarker assays in particular C20, C22, C24, C26 in cerebrospinal fluid (CSF). Until now no absolute quantitation assay for total VLCFAs in CSF has been successfully developed and qualified for clinical use. Methodology: A quantitative LC–MS/MS assay for total VLCFA in human CSF was developed. Derivatization tag and coupling chemistry were optimized for sensitivity. CSF contamination by blood, non-specific binding of VLCFA to surfaces and exogenous VLCFA contamination was minimized. Discussion/conclusion: This fit for purpose biomarker assay was used to measure baseline healthy human VLCFA levels across multiple subjects to establish an understanding of concentration ranges and feasibility.
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Sharp, P., A. Poulos, A. Fellenberg e D. Johnson. "Structure and lipid distribution of polyenoic very-long-chain fatty acids in the brain of peroxisome-deficient patients (Zellweger syndrome)". Biochemical Journal 248, n.º 1 (15 de novembro de 1987): 61–67. http://dx.doi.org/10.1042/bj2480061.
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The polyenoic fatty acids with carbon chain lengths from 26 to 38 (very-long-chain fatty acids, VLCFA) previously detected in abnormal amounts in Zellweger syndrome brain have been shown to be n-6 derivatives and therefore probably derived by chain elongation of shorter-chain n-6 fatty acids such as linoleic acid and arachidonic acid. Polyenoic VLCFA are also present in Zellweger syndrome liver, but this tissue differs significantly from brain in that the saturated and mono-unsaturated derivatives are the major VLCFA. Zellweger syndrome brain polyenoic VLCFA are present in the neutral lipids predominantly in cholesterol esters, with smaller amounts in the non-esterified fatty acid and triacylglycerol fractions. These fatty acids are barely detectable in any of the major phospholipids, but are present in significant amounts in an unidentified minor phospholipid. The polyenoic VLCFA composition of this lipid differs markedly from that observed for all other lipids, as it contains high proportions of pentaenoic and hexaenoic fatty acids with 34, 36 and 38 carbon atoms. A polar lipid with the chromatographic properties in normal brain contains similar fatty acids. It is postulated that the polyenoic VLCFA may play an important role in normal brain and accumulate in Zellweger syndrome brain because of a deficiency in the peroxisomal beta-oxidation pathway, although a possible peroxisomal role in the control of carbon-chain elongation cannot be discounted.
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Jones, Eric A. L., e Micheal D. K. Owen. "Investigating the Efficacy of Selected Very-Long-Chain Fatty Acid-Inhibiting Herbicides on Iowa Waterhemp (Amaranthus tuberculatus) Populations with Evolved Multiple Herbicide Resistances". Agronomy 11, n.º 3 (21 de março de 2021): 595. http://dx.doi.org/10.3390/agronomy11030595.
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Very long chain fatty acid (VLCFA)-inhibiting herbicides (Herbicide group (HG) 15) have been applied to corn and soybean fields in Iowa since the 1960s. The VLCFA-inhibiting herbicides are now applied more frequently to control multiple herbicide-resistant (MHR) waterhemp (Amaranthus tuberculatus Moq. J.D. Sauer) populations that are ubiquitous across the Midwest United States as resistance to the VLCFA-inhibiting herbicides is not widespread. Waterhemp has evolved multiple resistances to herbicides from seven sites of action (HG 2, 4, 5, 9, 14, 15, and 27), and six-way herbicide-resistant populations have been confirmed. Thus, the objective of this study was to determine if selected Iowa waterhemp populations are less sensitive to VLCFA-inhibiting herbicides when additional herbicide resistance traits have evolved within the selected population. Dose–response assays were conducted in a germination chamber to determine the efficacy of three selected VLCFA-inhibiting herbicides (acetochlor, S-metolachlor, and flufenacet) on selected Iowa MHR waterhemp populations. An herbicide-susceptible, three-way, four-way, and five-way herbicide-resistant waterhemp population responded to the herbicide treatments differently; however, several of the four-way and five-way herbicide-resistant populations exhibited resistance ratios greater than 1 when treated with acetochlor and S-metolachlor. Selected four-way herbicide-resistant waterhemp populations from Iowa were subjected to a dose–response assay in the field using the same VLCFA-inhibiting herbicides, and all herbicides achieved control greater than 80% at the maximum labeled rate. The results of the experiments provide evidence that some MHR waterhemp populations may exhibit decreased susceptibility the VLCFA-inhibiting herbicides, but generally, these herbicides remain efficacious on Iowa MHR waterhemp populations.
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Micoogullari, Yagmur, Sankha S. Basu, Jessie Ang, Nina Weisshaar, Nicholas D. Schmitt, Walid M. Abdelmoula, Begona Lopez, Jeffrey N. Agar, Nathalie Agar e John Hanna. "Dysregulation of very-long-chain fatty acid metabolism causes membrane saturation and induction of the unfolded protein response". Molecular Biology of the Cell 31, n.º 1 (1 de janeiro de 2020): 7–17. http://dx.doi.org/10.1091/mbc.e19-07-0392.
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Increasing evidence suggests that lipid homeostasis is critical for protein quality control. Very-long-chain fatty acids (VLCFA) are rare and poorly understood species. Here, it is shown that dysregulation of VLCFA metabolism causes increased membrane saturation, endoplasmic reticulum stress, and unfolded protein response induction.
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Zhu, Xiaoyu, Frédérique Tellier, Ying Gu e Shundai Li. "Disruption of Very-Long-Chain-Fatty Acid Synthesis Has an Impact on the Dynamics of Cellulose Synthase in Arabidopsis thaliana". Plants 9, n.º 11 (18 de novembro de 2020): 1599. http://dx.doi.org/10.3390/plants9111599.
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In higher plants, cellulose is synthesized by membrane-spanning large protein complexes named cellulose synthase complexes (CSCs). In this study, the Arabidopsis PASTICCINO2 (PAS2) was identified as an interacting partner of cellulose synthases. PAS2 was previously characterized as the plant 3-hydroxy-acyl-CoA dehydratase, an ER membrane-localized dehydratase that is essential for very-long-chain-fatty acid (VLCFA) elongation. The pas2-1 mutants show defective cell elongation and reduction in cellulose content in both etiolated hypocotyls and light-grown roots. Although disruption of VLCFA synthesis by a genetic alteration had a reduction in VLCFA in both etiolated hypocotyls and light-grown roots, it had a differential effect on cellulose content in the two systems, suggesting the threshold level of VLCFA for efficient cellulose synthesis may be different in the two biological systems. pas2-1 had a reduction in both CSC delivery rate and CSC velocity at the PM in etiolated hypocotyls. Interestingly, Golgi but not post-Golgi endomembrane structures exhibited a severe defect in motility. Experiments using pharmacological perturbation of VLCFA content in etiolated hypocotyls strongly indicate a novel function of PAS2 in the regulation of CSC and Golgi motility. Through a combination of genetic, biochemical and cell biology studies, our study demonstrated that PAS2 as a multifunction protein has an important role in the regulation of cellulose biosynthesis in Arabidopsis hypocotyl.
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van de Stadt, Stephanie I. W., Petra A. W. Mooyer, Inge M. E. Dijkstra, Conny J. M. Dekker, Divya Vats, Moin Vera, Maura R. Z. Ruzhnikov et al. "Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene". Genes 12, n.º 12 (30 de novembro de 2021): 1930. http://dx.doi.org/10.3390/genes12121930.
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Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.
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Stradomska, T. J., J. Kubalska, R. Janas e A. Tylki-Szymańska. "Reproductive function in men affected by X-linked adrenoleukodystrophy/adrenomyeloneuropathy". European Journal of Endocrinology 166, n.º 2 (fevereiro de 2012): 291–94. http://dx.doi.org/10.1530/eje-11-0490.
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BackgroundX-linked adrenoleukodystrophy (X-ALD) is the most frequent, severely neurodegenerative, clinically heterogeneous peroxisomal disorder, the signs of which are a consequence of myelin, adrenal cortex, and testes impairment.ObjectiveWe studied testosterone, LH, and FSH levels in X-ALD/adrenomyeloneuropathy (AMN) patients. We evaluate the ability to procreate of these patients by analysis of pedigree and family screening by detection of very long-chain fatty acid (VLCFA) levels.Subject and methodsSeventeen patients with X-ALD/AMN (16 with AMN and one asymptomatic) aged 24–48 (mean±s.d., 34.7±5.9) years, were identified based on the clinical picture, magnetic resonance imaging, and the presence of increased serum VLCFA levels. Nine X-ALD/AMN patients' daughters, mean ages ±s.d.=7.7±3.8 years, were identified as heterozygote by elevated VLCFA levels.Serum VLCFA levels were determined as ester derivatives by a gas chromatography method. Serum testosterone, LH, and FSH levels in X-ALD/AMN patients were detected by IRMAs.ResultsSerum testosterone levels were at the lowest levels of normal range but serum LH and FSH concentrations were increased in 57.1 and in 42.9% of X-ALD/AMN patients respectively. Among the 11 investigated of X-ALD/AMN married adult men, nine had produced offspring, a total of 13 children. All patients' daughters showed elevated serum VLCFA at heterozygote levels.ConclusionIn this study, we report that in a group of X-ALD/AMN married adult men, we did not find a significant decrease in fertility compared with the Polish population (18.2 vs 15%).
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Street, J. M., H. Singh e A. Poulos. "Metabolism of saturated and polyunsaturated very-long-chain fatty acids in fibroblasts from patients with defects in peroxisomal β-oxidation". Biochemical Journal 269, n.º 3 (1 de agosto de 1990): 671–77. http://dx.doi.org/10.1042/bj2690671.
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The metabolism of [1-14C]lignoceric acid (C24:0) and [1-14C]tetracosatetraenoic acid (C24:4, n-6) was studied in normal skin fibroblast cultures and in cultures from patients with defects in peroxisomal β-oxidation (but normal peroxisomal numbers). Cells from X-linked adrenoleukodystrophy (ALD) patients with a presumed defect in a peroxisomal acyl-CoA synthetase, specific for fatty acids of carbon chain lengths greater than 22 (very-long-chain fatty acids; VLCFA), showed a relatively normal production of radiolabelled CO2 and water-soluble metabolites from [1-14C]C24:0. However, the products of synthesis from acetate de novo (released by β-oxidation), i.e. C16 and C18 fatty acids, were decreased, and carbon chain elongation of the fatty acid was increased. In contrast, cell lines from two patients with an unidentified lesion in peroxisomal β-oxidation (peroxisomal disease, PD) showed a marked deficiency in CO2 and water-soluble metabolite production, a decreased synthesis of C16 and C18 fatty acids and an increase in carbon chain elongation. The relatively normal β-oxidation activity of ALD cells appears to be related to low uptake of substrate, as a defect in β-oxidation is apparent when measurements are performed on cell suspensions under high uptake conditions. Oxidation of [1-14C]C24:4 was relatively normal in ALD cells and in the cells from one PD patient but abnormal in those from the other. Our data suggest that, despite the deficiency in VLCFA CoA synthetase, ALD cells retain a near normal ability to oxidize both saturated and polyunsaturated VLCFA under some culture conditions. However, acetate released by β-oxidation of the saturated VLCFA and, to a much lesser degree, the polyunsaturated VLCFA, appears to be used preferentially for the production of CO2 and water-soluble products, and acetate availability for fatty acid synthesis in other subcellular compartments is markedly decreased. It is likely that the increased carbon chain elongation of the saturated VLCFA which is also observed reflects the increased availability of substrate (C24:0) and/or an increase in microsomal elongation activity in ALD cells.
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Villoria-González, Andrea, Bettina Zierfuss, Patricia Parzer, Elisabeth Heuböck, Violetta Zujovic, Petra Waidhofer-Söllner, Markus Ponleitner et al. "Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders". Biomolecules 13, n.º 12 (23 de novembro de 2023): 1696. http://dx.doi.org/10.3390/biom13121696.
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Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
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Hama, Kotaro, Yuko Fujiwara, Shigeo Takashima, Yasuhiro Hayashi, Atsushi Yamashita, Nobuyuki Shimozawa e Kazuaki Yokoyama. "Hexacosenoyl-CoA is the most abundant very long-chain acyl-CoA in ATP binding cassette transporter D1-deficient cells". Journal of Lipid Research 61, n.º 4 (19 de fevereiro de 2020): 523–36. http://dx.doi.org/10.1194/jlr.p119000325.
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X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by deleterious mutations in the ABCD1 gene. The ABCD1 protein transports very long-chain FAs (VLCFAs) from the cytosol into the peroxisome where the VLCFAs are degraded through β-oxidation. ABCD1 dysfunction leads to VLCFA accumulation in individuals with X-ALD. FAs are activated by esterification to CoA before metabolic utilization. However, the intracellular pools and metabolic profiles of individual acyl-CoA esters have not been fully analyzed. In this study, we profiled the acyl-CoA species in fibroblasts from X-ALD patients and in ABCD1-deficient HeLa cells. We found that hexacosenoyl (26:1)-CoA, but not hexacosanoyl (26:0)-CoA, was the most abundantly concentrated among the VLCFA-CoA species in these cells. We also show that 26:1-CoA is mainly synthesized from oleoyl-CoA, and the metabolic turnover rate of 26:1-CoA was almost identical to that of oleoyl-CoA in both WT and ABCD1-deficient HeLa cells. The findings of our study provide precise quantitative and metabolic information of each acyl-CoA species in living cells. Our results suggest that VLCFA is endogenously synthesized as VLCFA-CoA through a FA elongation pathway and is then efficiently converted to other metabolites, such as phospholipids, in the absence of ABCD1.
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Vanderlinde, Elizabeth M., Artur Muszyński, Joe J. Harrison, Susan F. Koval, Dallas L. Foreman, Howard Ceri, Elmar L. Kannenberg, Russell W. Carlson e Christopher K. Yost. "Rhizobium leguminosarum biovar viciae 3841, deficient in 27-hydroxyoctacosanoate-modified lipopolysaccharide, is impaired in desiccation tolerance, biofilm formation and motility". Microbiology 155, n.º 9 (1 de setembro de 2009): 3055–69. http://dx.doi.org/10.1099/mic.0.025031-0.
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The lipopolysaccharide (LPS) of the Gram-negative legume symbiont Rhizobium leguminosarum biovar viciae 3841 contains several unique modifications, including the addition of a 27-hydroxyoctacosanoic acid (27OHC28 : 0), also termed the very long chain fatty acid (VLCFA), attached at the 2′ position of lipid A. A transposon mutant that lacks expression of two putative 3-oxo-acyl [acyl-carrier protein] synthase II genes, fabF1 and fabF2, from the VLCFA biosynthetic cluster, was isolated and characterized. MS indicated that the lipid A of the mutant lacked the VLCFA modification, and sodium deoxycholate (DOC)-PAGE of the LPS indicated further structural alterations. The mutant was characteristically sensitive to several stresses that would be experienced in the soil environment, such as desiccation and osmotic stresses. An increase in the excretion of neutral surface polysaccharides was observed in the mutant. This mutant was also altered in its attachment to solid surfaces, and was non-motile, with most of the mutant cells lacking flagella. Despite the pleiotropic effects of the mutation, these mutants were still able to nodulate legumes and fix atmospheric nitrogen. This report emphasizes that a structurally intact VLCFA-containing lipid A is critical to cellular traits that are important for survival in the rhizosphere.
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Takahashi, Hideomi, Aiko Ohki, Mitsuru Kanzaki, Akira Tanaka, Yukiharu Sato, Bernd Matthes, Peter Böger e Ko Wakabayashi. "Very-Long-Chain Fatty Acid Biosynthesis is Inhibited by Cafenstrole, N,N-Diethyl-3-mesitylsulfonyl-1H-1,2,4-triazole-1-carboxamide and Its Analogs". Zeitschrift für Naturforschung C 56, n.º 9-10 (1 de outubro de 2001): 781–86. http://dx.doi.org/10.1515/znc-2001-9-1016.
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AbstractThe rice herbicide cafenstrole and its analogs inhibited the incorporation of [1-14C]-oleate and [2-14C]-malonate into very-long-chain fatty acids (VLCFAs), using Scenedesmus cells and leek microsomes from Allium porrum. Although the precise mode of interaction of cafenstrole at the molecular level is not completely clarified by the present study, it is concluded that cafenstrole acts as a specific inhibitor of the microsomal elongase enzyme involved in the biosynthesis of fatty acids with alkyl chains longer than C18. For a strong VLCFA biosynthesis inhibition an -SO2- linkage of the 1,2,4-triazole-1-carboxamides was required. Furthermore, N,N-dialkyl substitution of the carbamoyl nitrogen and electron-donating groups such as methyl at the benzene ring of 1,2,4-triazole-1-carboxamides produced a strong inhibition of VLCFA formation. A correlation was found between the phytotoxic effect against barnyardgrass (Echinochloa oryzicola) and impaired VLCFA formation.
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Hall, N. A., G. W. Lynes e N. M. Hjelm. "Ratios for very-long-chain fatty acids in plasma of subjects with peroxisomal disorders, as determined by HPLC and validated by gas chromatography-mass spectrometry." Clinical Chemistry 34, n.º 6 (1 de junho de 1988): 1041–45. http://dx.doi.org/10.1093/clinchem/34.6.1041.
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Abstract We describe an HPLC method for measurement of ratios of concentrations of very-long-chain fatty acids (VLCFA) in plasma. The method, which involves ultraviolet detection of p-bromophenacyl derivatives of fatty acids, is validated by comparison with a gas chromatographic-mass spectrometric (GC-MS) method. The correlation between the ratios of 24-carbon fatty acids to 22-carbon fatty acids (C24/C22) estimated by the two methods was close (r = 0.976) as was the correlation for the C26/C22 ratios (r = 0.947). Increased VLCFA ratios could be demonstrated by either technique in patients with adrenoleukodystrophy, Zellweger syndrome, and infantile Refsum's disease. The HPLC method also measures phytanate concentrations in plasma. Control VLCFA ratios (for subjects without peroxisomal disorders) obtained by the two methods agree well with those reported by Moser et al. (Ann Neurol 1984; 16:628-41). For subjects younger than one year, ratios for C24/C22 and C26/C22 fatty acids were significantly greater than in older subjects.
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Buda, Agnieszka, Sonja Forss-Petter, Rong Hua, Yorrick Jaspers, Mark Lassnig, Petra Waidhofer-Söllner, Stephan Kemp, Peter Kim, Isabelle Weinhofer e Johannes Berger. "ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis". Biomolecules 13, n.º 9 (31 de agosto de 2023): 1333. http://dx.doi.org/10.3390/biom13091333.
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X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD.
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Spreghini, Maria Rita, Nicoletta Gianni, Tommaso Todisco, Cristiano Rizzo, Marco Cappa e Melania Manco. "Nutritional Counseling and Mediterranean Diet in Adrenoleukodystrophy: A Real-Life Experience". Nutrients 16, n.º 19 (1 de outubro de 2024): 3341. http://dx.doi.org/10.3390/nu16193341.
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Background/Objectives: Adrenoleukodystrophy (X-ALD) is a metabolic disorder caused by dysfunctional peroxisomal beta-oxidation of very-long-chain fatty acids (VLCFAs). A VLCFA-restricted Mediterranean diet has been proposed for patients and carriers to reduce daily VLCFA intake. Methods: We retrospectively evaluated plasma VLCFAs in a cohort of 36 patients and 20 carriers at baseline and after 1 year of restricted diet. Results: At T1, compliant adult patients had significantly lower C26:0 levels [1.7 (1.2) vs. 2.5 µmol/L (1.7), p < 0.05], C26:0/C22:0 ratio [0.04 (0.02) vs. 0.06 (0.03), p < 0.05], and triglycerides [93 (56.5) vs. 128 mg/dL (109.5), p < 0.05] than non-compliant ones. C26:0 [2.4 (1.7) vs. 1.7 (1.2) µmol/L, p < 0.05], the C26:0/C22:0 ratio [0.06 (0.04) vs. 0.04 (0.02), p < 0.05], and cholesterol [173.5 (68.3) mg/dL vs. 157 (54) mg/dL, p < 0.05] were significantly reduced in compliant adult patients at T1 vs. baseline. As for carriers, the C26:0/C22:0 ratio was lower [0.02 (0.01) vs. 0.04 (0.009), p < 0.05] at T1 in compliant carriers, as compared to non-compliant ones. The C26:0/C22:0 [0.03 (0.02) vs. 0.02 (0.01) p < 0.05] and C24:0/C22:0 [1.0 (0.2) vs. 0.9 (0.3), p < 0.05] ratios were significantly decreased at T1 vs. T0. Conclusions: A VLCFA-restricted diet is effective in reducing plasma VLCFA levels and their ratios and must be strongly encouraged as support to therapy.
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Stradomska, T. J., e A. Tylki-Szymańska. "Decreasing serum VLCFA levels in ageing X-ALD female carriers". Journal of Inherited Metabolic Disease 24, n.º 8 (dezembro de 2001): 851–57. http://dx.doi.org/10.1023/a:1013992224811.
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Soltani, Nader, Lynette R. Brown e Peter H. Sikkema. "Weed Control in Corn and Soybean with Group 15 (VLCFA Inhibitor) Herbicides Applied Preemergence". International Journal of Agronomy 2019 (7 de abril de 2019): 1–7. http://dx.doi.org/10.1155/2019/8159671.
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Limited information exists on the efficacy of pethoxamid for annual grass and broadleaf control in corn and soybean in Ontario. A total of 10 field experiments (5 with corn and 5 with soybean) were conducted during 2015 to 2017 in Ontario, Canada, to compare the weed control efficacy of dimethenamid-P at 544 g·ai·ha−1, pethoxamid at 840 g·ai·ha−1, pyroxasulfone at 100 g·ai·ha−1, and S-metolachlor at 1050 g·ai·ha−1 applied preemergence (PRE). Reduced weed interference with pyroxasulfone and dimethenamid-P resulted in corn yield that was similar to the weed-free control; however, weed interference with pethoxamid and S-metolachlor reduced corn yield 28 and 33%, respectively. Reduced weed interference with pyroxasulfone resulted in soybean yield that was similar to the weed-free control; however, weed interference with pethoxamid, dimethenamid-P, and S-metolachlor reduced soybean yield 27, 27, and 30%, respectively. At 4 and 8 weeks after application (WAA), all VLCFA inhibitor herbicides (Group 15) provided excellent redroot pigweed control (90 to 99%) in corn. There were no differences in common ragweed control, density, and dry weight among the VLCFA inhibitor herbicide evaluated; pyroxasulfone provided highest numeric common ragweed control and lowest numeric density and dry weight. At 4 and 8 WAA, pyroxasulfone provided the best common lambsquarters and wild mustard control and lowest numeric density and dry weight in corn and soybean. At 8 WAA, the VLCFA inhibitor herbicides controlled green foxtail 91 to 96% in corn; dimethenamid-P provided better control of green foxtail than pethoxamid in soybean. There were no differences in barnyard grass control among the VLCFA inhibitor herbicides evaluated.
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Robinson, B. S., D. W. Johnson e A. Poulos. "Metabolism of hexacosatetraenoic acid (C26:4,n-6) in immature rat brain". Biochemical Journal 267, n.º 2 (15 de abril de 1990): 561–64. http://dx.doi.org/10.1042/bj2670561.
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Rat brain was recently found to contain polyenoic very-long-chain fatty acids (VLCFA) belonging to the n-3 and n-6 series with four, five and six double bonds and even-carbon chain lengths from 24 to 38 [Robinson, Johnson & Poulos (1990) Biochem. J. 265, 763-767]. In the present paper, the metabolism in vivo of hexacosatetraenoic acid (C26:4,n-6) was studied in neonatal rat brain. Rats were injected intracerebrally with [1-14C]C26:4,n-6 and the labelled metabolites were examined after 4 h. Radioactivity was detected mainly in non-esterified fatty acids, with smaller amounts in other neutral lipids and phospholipids. Radiolabelled fatty acid products included C28-36 tetraenoic and C26-28 pentaenoic VLCFA formed by elongation and desaturation of the substrate, and C14-24 saturated, C16-24 monoenoic, C18-24 dienoic, C18-22 trienoic and C20-24 tetraenoic fatty acids formed from released [1-14C]acetate either by synthesis de novo or by elongation of endogenous fatty acids. The data suggest that polyenoic VLCFA are synthesized in brain from shorter-chain precursor fatty acids and undergo beta-oxidation.
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Dohr, Katrin A., Silvija Tokic, Magdalena Gastager-Ehgartner, Tatjana Stojakovic, Miroslav Dumic, Barbara Plecko e Katja K. Dumic. "Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy". International Journal of Molecular Sciences 24, n.º 6 (22 de março de 2023): 5957. http://dx.doi.org/10.3390/ijms24065957.
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X-linked adrenoleukodystrophy (X-ALD) is a rare inborn error of the peroxisomal metabolism caused by pathologic variants in the ATP-binding cassette transporter type D, member 1 (ABCD1) gene located on the X-chromosome. ABCD1 protein, also known as adrenoleukodystrophy protein, is responsible for transport of the very long chain fatty acids (VLCFA) from cytoplasm into the peroxisomes. Therefore, altered function or lack of the ABCD1 protein leads to accumulation of VLCFA in various tissues and blood plasma leading to either rapidly progressive leukodystrophy (cerebral ALD), progressive adrenomyeloneuropathy (AMN), or isolated primary adrenal insufficiency (Addison’s disease). We report two distinct single nucleotide deletions in the ABCD1 gene, c.253delC [p.Arg85Glyfs*18] in exon 1, leading to both cerebral ALD and to AMN phenotype in one family, and c.1275delA [p.Phe426Leufs*15] in exon 4, leading to AMN and primary adrenal insufficiency in a second family. For the latter variant, we demonstrate reduced mRNA expression and a complete absence of the ABCD1 protein in PBMC. Distinct mRNA and protein expression in the index patient and heterozygous carriers does not associate with VLCFA concentration in plasma, which is in line with the absence of genotype–phenotype correlation in X-ALD.
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Bertucci, Matthew B., Michael Fogleman e Jason K. Norsworthy. "Efficacy of fall-applied residual herbicides on weedy rice control in rice (Oryza sativa L.)". Weed Technology 33, n.º 03 (27 de maio de 2019): 441–47. http://dx.doi.org/10.1017/wet.2019.24.
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AbstractField experiments were initiated near Colt, AR, in the fall of 2016 and continued through the summer of 2018 to evaluate rice tolerance and weedy (or red) rice control after fall-applied very-long-chain fatty acid (VLCFA)-inhibiting herbicides. A split-plot design was used for the experiment, with the whole-plot factor being winter condition (flooded or non-flooded) and the split-plot factors being herbicide and rate. Herbicide treatments included acetochlor, dimethenamid-P, pethoxamid, pyroxasulfone, andS-metolachlor applied at 1,050, 525, 420, 205, and 1,070 g ai ha−1and at 2,100, 1,050, 840, 410, and 2,140 g ha−1for low rates and high rates, respectively. Herbicides were applied in the fall, then ‘CL172’ rice was drill seeded in the spring of the following calendar year. Weedy rice control differed between years, but acetochlor and pyroxasulfone consistently provided the greatest levels of control across rates and flood conditions. Consequently, herbicides that best controlled weedy rice also caused the greatest injury to cultivated rice. Rice injury did not exceed 13% regardless of herbicide treatment at 3 wk after planting (WAP). However, the high rate of pyroxasulfone caused 20% rice injury at 5 WAP in 2018. Although it was expected that winter condition may affect residual activity of the VLCFA-inhibiting herbicides, herbicide selection and application rate both had much greater effects on rice injury and on weedy rice control. Based on these results, rice injury would be minimal or nonexistent after fall applications of the tested VLCFA inhibitors, and intermediate levels of weedy rice control may be achieved. The implementation of VLCFA-inhibiting herbicides in rice production systems would offer a novel herbicide site of action and offer a degree of selective control of weedy rice.
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Stradomska, Tresa J. "Choroby peroksysomalne". Postępy Biochemii 64, n.º 4 (29 de dezembro de 2018): 359–67. http://dx.doi.org/10.18388/pb.2018_150.
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Peroksysomy to wielofunkcyjne organelle, które spełniają kluczową rolę w licznych procesach biochemicznych dostosowując się dynamicznie do aktualnych wymogów fizjologicznych komórki. Zaburzenie struktury peroksysomów na skutek mutacji i dysfunkcji genów PEX lub innych genów kodujących białka biogenezy czy pojedyncze peroksysomalne białka funkcyjne stanowi podłoże patogenetyczne chorób peroksysomalnych. Proces β-oksydacji bardzo długołańcuchowych kwasów tłuszczowych (VLCFA) jest unikalnym szlakiem metabolicznym zlokalizowanym wyłącznie w peroksysomie. To warunkuje, że VLCFA jest głównym biomarkerem w diagnostyce chorób peroksysomalnych. Choroby peroksysomalne prezentują szerokie spektrum objawów klinicznych od neonatalnego, ciężkiego Zespołu Zellwegera z dysmorfią, dysfunkcją wielonarządową do późnoobjawowej adrenoleukodystrofii występującej u dorosłych, sprzężonej z chromosomem X. Dzięki zastosowaniu wysokospecjalistycznych technik analitycznych jest to stale powiększająca się grupa rzadkich chorób genetycznych.
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Kohlwein, Sepp D., Sandra Eder, Chan-Seok Oh, Charles E. Martin, Ken Gable, Dagmar Bacikova e Teresa Dunn. "Tsc13p Is Required for Fatty Acid Elongation and Localizes to a Novel Structure at the Nuclear-Vacuolar Interface inSaccharomyces cerevisiae". Molecular and Cellular Biology 21, n.º 1 (1 de janeiro de 2001): 109–25. http://dx.doi.org/10.1128/mcb.21.1.109-125.2001.
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ABSTRACT The TSC13/YDL015c gene was identified in a screen for suppressors of the calcium sensitivity of csg2Δ mutants that are defective in sphingolipid synthesis. The fatty acid moiety of sphingolipids in Saccharomyces cerevisiae is a very long chain fatty acid (VLCFA) that is synthesized by a microsomal enzyme system that lengthens the palmitate produced by cytosolic fatty acid synthase by two carbon units in each cycle of elongation. TheTSC13 gene encodes a protein required for elongation, possibly the enoyl reductase that catalyzes the last step in each cycle of elongation. The tsc13 mutant accumulates high levels of long-chain bases as well as ceramides that harbor fatty acids with chain lengths shorter than 26 carbons. These phenotypes are exacerbated by the deletion of either the ELO2 or ELO3gene, both of which have previously been shown to be required for VLCFA synthesis. Compromising the synthesis of malonyl coenzyme A (malonyl-CoA) by inactivating acetyl-CoA carboxylase in atsc13 mutant is lethal, further supporting a role of Tsc13p in VLCFA synthesis. Tsc13p coimmunoprecipitates with Elo2p and Elo3p, suggesting that the elongating proteins are organized in a complex. Tsc13p localizes to the endoplasmic reticulum and is highly enriched in a novel structure marking nuclear-vacuolar junctions.
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Erdbrügger, Pia, e Florian Fröhlich. "The role of very long chain fatty acids in yeast physiology and human diseases". Biological Chemistry 402, n.º 1 (18 de novembro de 2020): 25–38. http://dx.doi.org/10.1515/hsz-2020-0234.
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AbstractFatty acids (FAs) are a highly diverse class of molecules that can have variable chain length, number of double bonds and hydroxylation sites. FAs with 22 or more carbon atoms are described as very long chain fatty acids (VLCFAs). VLCFAs are synthesized in the endoplasmic reticulum (ER) through a four-step elongation cycle by membrane embedded enzymes. VLCFAs are precursors for the synthesis of sphingolipids (SLs) and glycerophospholipids. Besides their role as lipid constituents, VLCFAs are also found as precursors of lipid mediators. Mis-regulation of VLCFA metabolism can result in a variety of inherited diseases ranging from ichthyosis, to myopathies and demyelination. The enzymes for VLCFA biosynthesis are evolutionary conserved and many of the pioneering studies were performed in the model organism Saccharomyces cerevisiae. A growing body of evidence suggests that VLCFA metabolism is intricately regulated to maintain lipid homeostasis. In this review we will describe the metabolism of VLCFAs, how they are synthesized, transported and degraded and how these processes are regulated, focusing on budding yeast. We will review how lipid metabolism and membrane properties are affected by VLCFAs and which impact mutations in the biosynthetic genes have on physiology. We will also briefly describe diseases caused by mis-regulation of VLCFAs in human cells.
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Lipiński, Patryk, Piotr Stawiński, Małgorzata Rydzanicz, Maria Wypchło, Rafał Płoski, Teresa Joanna Stradomska, Elżbieta Jurkiewicz et al. "Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants". Journal of Applied Genetics 61, n.º 1 (18 de outubro de 2019): 87–91. http://dx.doi.org/10.1007/s13353-019-00523-w.
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Abstract Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene—c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.
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Ni, Fei, Mao Yang, Jun Chen, Yifei Guo, Shubei Wan, Zisu Zhao, Sijie Yang, Lingna Kong, Pu Chu e Rongzhan Guan. "BnUC1 Is a Key Regulator of Epidermal Wax Biosynthesis and Lipid Transport in Brassica napus". International Journal of Molecular Sciences 25, n.º 17 (2 de setembro de 2024): 9533. http://dx.doi.org/10.3390/ijms25179533.
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The bHLH (basic helix–loop–helix) transcription factor AtCFLAP2 regulates epidermal wax accumulation, but the underlying molecular mechanism remains unknown. We obtained BnUC1mut (BnaA05g18250D homologous to AtCFLAP2) from a Brassica napus mutant with up-curling leaves (Bnuc1) and epidermal wax deficiency via map-based cloning. BnUC1mut contains a point mutation (N200S) in the conserved dimerization domain. Overexpressing BnUC1mut in ZS11 (Zhongshuang11) significantly decreased the leaf epidermal wax content, resulting in up-curled and glossy leaves. In contrast, knocking out BnUC1mut in ZS11-NIL (Zhongshuang11-near-isogenic line) restored the normal leaf phenotype (i.e., flat) and significantly increased the leaf epidermal wax content. The point mutation weakens the ability of BnUC1mut to bind to the promoters of VLCFA (very-long-chain fatty acids) synthesis-related genes, including KCS (β-ketoacyl coenzyme synthase) and LACS (long-chain acyl CoA synthetase), as well as lipid transport-related genes, including LTP (non-specific lipid transfer protein). The resulting sharp decrease in the transcription of genes affecting VLCFA biosynthesis and lipid transport disrupts the normal accumulation of leaf epidermal wax. Thus, BnUC1 influences epidermal wax formation by regulating the expression of LTP and genes associated with VLCFA biosynthesis. Our findings provide a foundation for future investigations on the mechanism mediating plant epidermal wax accumulation.
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Vargas, Carmen R., Alethéa G. Barschak, Daniella M. Coelho, Vivian Furlanetto, Carolina F. M. de Souza, Simone M. Karam, Laura Jardim, Moacir Wajner e Roberto Giugliani. "Clinical and biochemical findings in 7 patients with X-linked adrenoleukodystrophy treated with Lorenzo's Oil". Genetics and Molecular Biology 23, n.º 4 (dezembro de 2000): 697–701. http://dx.doi.org/10.1590/s1415-47572000000400001.
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X-Linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of the peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA) in tissues and biological fluids. The major accumulated acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0). The disorder is characterized clinically by central and peripheral demyelination and adrenal insufficiency closely related to the accumulation of fatty acids. The incidence of X-ALD is estimated to be 1:25,000 males. At least six phenotypes can be distinguished. The most common phenotypes are childhood cerebral ALD and adrenomyeloneuropathy (AMN). The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate (GTO/GTE) mixture, known as Lorenzo's Oil, combined with a VLCFA-poor diet. There are alternative treatments such as bone marrow transplantation and immunosuppression, as well as the use of lovastatin and sodium phenylacetate. In the present study we report the clinical and biochemical course of 7 male patients with X-ALD treated with Lorenzo's Oil and a VLCFA-restricted diet. Treatment produced 50% reduction in C26:0 and 42.8% reduction in the C26:0/C22:0 ratio. Most patients remained clinically well, although approximately 30% of them presented a rapid clinical deterioration. The results showed a poor biochemical-clinical correlation for treatment, indicating that new therapies for X-ALD are needed in order to obtain a better prognosis for patients.
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Hay, Marshall M., Jeffrey J. Albers, J. Anita Dille e Dallas E. Peterson. "Control of Atrazine-Resistant Palmer Amaranth (Amaranthus palmeri) in Double-Crop Grain Sorghum". Weed Technology 33, n.º 1 (fevereiro de 2019): 115–22. http://dx.doi.org/10.1017/wet.2018.102.
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AbstractDouble-crop grain sorghum after winter wheat harvest is a common cropping system in the southern plains region. Palmer amaranth is a troublesome weed in double-crop grain sorghum in Kansas. Populations resistant to various herbicides (e.g., atrazine, glyphosate, metsulfuron, pyrasulfotole) have made Palmer amaranth management even more difficult for producers. To evaluate control of atrazine-resistant and atrazine-susceptible Palmer amaranth in double-crop grain sorghum, we assessed 14 herbicide programs, of which 8 were PRE only and 6 were PRE followed by (fb) POST applications. Visible ratings of Palmer amaranth control were taken at 3 and 8 wk after planting (WAP) grain sorghum. PRE treatments containing very-long-chain fatty acid (VLCFA)–inhibiting herbicides provided 91% control of atrazine-resistant Palmer amaranth 3 WAP, and reduced weed density 8 WAP compared to atrazine-only PRE treatments. PRE fb POST treatments, especially those that included VLCFA-inhibiting herbicides, provided greater control (71% to 93%) of both atrazine-resistant and atrazine-susceptible Palmer amaranth, respectively, at 8 WAP compared to PRE treatments alone (59% to 79%). These results demonstrated the utility of VLCFA-inhibiting herbicides applied PRE and in a layered PRE fb POST approach in controlling atrazine-resistant Palmer amaranth, as well as the importance of an effective POST application following residual PRE herbicides for controlling both atrazine-resistant and atrazine-susceptible Palmer amaranth in double-crop grain sorghum.
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Gagianone, R. B., e M. G. L. Ribeiro. "USING SCIENTIFIC PAPERS TO STIMULATE THE STUDY OF BIOCHEMISTRY AND THE UNDERSTANDING OF SCIENTIFIC KNOWLEDGE CONSTRUCTION: THE RESEARCH ON ADRENOLEUKODYSTROPHY". Revista de Ensino de Bioquímica 13 (24 de agosto de 2015): 6. http://dx.doi.org/10.16923/reb.v13i2.574.
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Introduction The X-linked adrenoleukodystrophy (X-ALD) is characterized by mutations in very long chain fatty acids (VLCFA) peroxisome transporter, leading to VLCFA accumulation in myelin sheath. In the 70’s and 80’s it was hypothesized that X-ALD is caused by enzymatic deficits in FA-coenzyme A connection, VLCFA degradation or FA elongation. The latter enabled Lorenzo’s oil (LO) treatment, which became famous by the homonym movie. The apparent initial therapy effectiveness lead to LO administration in many patients, although with biochemical knowledge progress its relevance has been questioned.Objectives Our aim was to discuss X-ALD researches in “Lipids Metabolism” classes during 2014 Biochemistry courses to Biology and Biomedicine undergraduate students at Fluminense Federal University to illustrate how scientific knowledge is constructed.Materials and MethodsIn order to contrast the recent scientific advances with the information spread to society through “Lorenzo’s Oil”, the movie in edited version was presented to students followed by a questionnaire with Likert scale to evaluate the perception of scientific knowledge exposed by the movie. Afterwards, a Guided Study containing a brief history and discursive questions based upon a paper (Wiesingner et.al, J. Biol. Chem. 288:19269, 2013) was applied in class.Results and DiscussionFrom 58 students who filled in the questionnaire,72,4% considered the movie shows that X-ALD biochemical knowledge has been achieved. This notion was confirmed since 84,5% agreed LO is an effective alternative treatment if X-ALD is early detected. The same percentage agreed that based on the movie the biochemical deficiency relies on an enzyme involved in VLCFA degradation. Although the movie transmits the idea that the cure has been found, 67,2% believed X-ALD biochemical mechanisms are not fully comprehended. ConclusionsThe Guided Study/movie application was very effective because allowed the understanding of mechanisms completely unknown by the time of LO development and also the comprehension of scientific knowledge construction through a playful and participative activity.AcknowledgementsWe thank Prograd-UFF for scholarship supply.Key wordsAdrenoleukodystrophy; Biochemistry teaching; scientific knowledge
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Strom, Seth A., Lisa C. Gonzini, Charlie Mitsdarfer, Adam S. Davis, Dean E. Riechers e Aaron G. Hager. "Characterization of multiple herbicide–resistant waterhemp (Amaranthus tuberculatus) populations from Illinois to VLCFA-inhibiting herbicides". Weed Science 67, n.º 4 (27 de maio de 2019): 369–79. http://dx.doi.org/10.1017/wsc.2019.13.
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AbstractField experiments were conducted in 2016 and 2017 in Champaign County, IL, to study a waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] population (CHR) resistant to 2,4-D and 4-hydroxyphenylpyruvate dioxygenase (HPPD)-, photosystem II–, acetolactate synthase (ALS)-, and protoporphyrinogen oxidase–inhibiting herbicides. Two field experiments were designed to investigate the efficacy of very-long-chain fatty-acid (VLCFA)-inhibiting herbicides, including a comparison of active ingredients at labeled use rates and a rate titration experiment. Amaranthus tuberculatus density and control were evaluated at 28 and 42 d after treatment (DAT). Nonencapsulated acetochlor, alachlor, and pyroxasulfone provided the greatest PRE control of CHR (56% to 75%) at 28 DAT, while metolachlor, S-metolachlor, dimethenamid-P, and encapsulated acetochlor provided less than 27% control. In the rate titration study, nonencapsulated acetochlor controlled CHR more than equivalent field use rates of S-metolachlor. Subsequent dose–response experiments with acetochlor, S-metolachlor, dimethenamid-P, and pyroxasulfone in the greenhouse included three multiple herbicide–resistant (MHR) A. tuberculatus populations: CHR-M6 (progeny generated from CHR), MCR-NH40 (progeny generated from Mclean County, IL), and ACR (Adams County, IL), in comparison with a sensitive population (WUS). Both CHR-M6 and MCR-NH40 are MHR to atrazine and HPPD, and ALS inhibitors and demonstrated higher survival rates (LD50) to S-metolachlor, acetochlor, dimethenamid-P, or pyroxasulfone than ACR (atrazine resistant but HPPD-inhibitor sensitive) and WUS. Based on biomass reduction (GR50), resistant to sensitive (R:S) ratios between CHR-M6 and WUS were 7.5, 6.1, 5.5, and 2.9 for S-metolachlor, acetochlor, dimethenamid-P, and pyroxasulfone, respectively. Values were greater for MCR-NH40 than CHR-M6, and ACR was the most sensitive to all VLCFA inhibitors tested. Complete control of all populations was achieved at or below a field use rate of acetochlor. In summary, field studies demonstrated CHR is not controlled by several VLCFA-inhibiting herbicides. Greenhouse dose–response experiments corroborated field results and generated R:S ratios (LD50) ranging from 4.5 to 64 for CHR-M6 and MCR-NH40 among the four VLCFA-inhibiting herbicides evaluated.
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Zheng, Huan, Yueting Liang, Ben Hong, Yingyi Xu, Mengfan Ren, Yixu Wang, Liyuan Huang, Lina Yang e Jianmin Tao. "Genome-Scale Analysis of the Grapevine KCS Genes Reveals Its Potential Role in Male Sterility". International Journal of Molecular Sciences 24, n.º 7 (30 de março de 2023): 6510. http://dx.doi.org/10.3390/ijms24076510.
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Very long-chain fatty acid (VLCFA) synthesis in plants, is primarily rate-limited by the enzyme 3-ketoacyl CoA synthase (KCS), which also controls the rate and carbon chain length of VLCFA synthesis. Disruption of VLCFA during pollen development, may affect the pollen wall formation and ultimately lead to male sterility. Our study identified 24 grapevine KCS (VvKCS) genes and provided new names based on their relative chromosome distribution. Based on sequence alignment and phylogenetic investigation, these genes were grouped into seven subgroups, members of the same subgroup having similar motif structures. Synteny analysis of VvKCS genes, showed that the segmental duplication events played an important role in expanding this gene family. Expression profiles obtained from the transcriptome data showed different expression patterns of VvKCS genes in different tissues. Comparison of transcriptome and RT-qPCR data of the male sterile grape ‘Y−14’ and its fertile parent ‘Shine Muscat’, revealed that 10 VvKCS genes were significantly differentially expressed at the meiosis stage, which is a critical period of pollen wall formation. Further, joint analysis by weighted gene co-expression network analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG), revealed that five of these VvKCS (VvKCS6/15/19/20/24) genes were involved in the fatty acid elongation pathway, which may ultimately affect the structural integrity of the pollen wall in ‘Y−14’. This systematic analysis provided a foundation for further functional characterization of VvKCS genes, with the aim of grapevine precision breeding improvement.
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Liu, Jinxin, Xin Wang, Di Huang, Yuna Qi, Lei Xu e Yankun Shao. "A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report". Medicine 103, n.º 16 (19 de abril de 2024): e37874. http://dx.doi.org/10.1097/md.0000000000037874.
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Rationale: X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene leading to very long chain fatty acid (VLCFA) accumulation. The disease demonstrates a spectrum of phenotypes including adrenomyeloneuropathy (AMN). We aimed to identify the genetic basis of disease in a patient presenting with AMN features in order to confirm the diagnosis, expand genetic knowledge of ABCD1 mutations, and elucidate potential genotype-phenotype associations to inform management. Patient concerns: A 29-year-old male presented with a 4-year history of progressive spastic paraplegia, weakness of lower limbs, fecal incontinence, sexual dysfunction, hyperreflexia, and positive Babinski and Chaddock signs. Diagnoses: Neuroimaging revealed brain white matter changes and spinal cord thinning. Significantly elevated levels of hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) suggested very long chain fatty acids (VLCFA) metabolism disruption. Genetic testing identified a novel hemizygous ABCD1 mutation c.249dupC (p.F83fs). These findings confirmed a diagnosis of X-linked ALD with an AMN phenotype. Interventions: The patient received dietary counseling to limit VLCFA intake. Monitoring for adrenal insufficiency and consideration of Lorenzo’s oil were advised. Genetic counseling and testing were offered to at-risk relatives. Outcomes: At present, the patient continues to experience progressive paraplegia. Adrenal function remains normal thus far without steroid replacement. Family members have undergone predictive testing. Lessons: This case expands the known mutation spectrum of ABCD1-linked X-ALD, providing insight into potential genotype-phenotype correlations. A thoughtful diagnostic approach integrating clinical, biochemical and genetic data facilitated diagnosis. Findings enabled genetic counseling for at-risk relatives regarding this X-linked disorder.
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Streck, Sibylle, K. Winnefeld, Iris Maurer e H. P. Volz. "Die quantitative Bestimmung ausgewählter langkettiger Fettsäuren und sehr langkettiger Fettsäuren (VLCFA) im Serum. The Quantitative Determination of Selected Long Chain and Very Long Chain Fatty Acids (VLCFA) in Serum". LaboratoriumsMedizin 24, n.º 8 (janeiro de 2000): 373–76. http://dx.doi.org/10.1515/labm.2000.24.8.373.
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Shon, Jinyoung, Yerim Han e Yoon Jung Park. "Effects of Dietary Fat to Carbohydrate Ratio on Obesity Risk Depending on Genotypes of Circadian Genes". Nutrients 14, n.º 3 (22 de janeiro de 2022): 478. http://dx.doi.org/10.3390/nu14030478.
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Although the impacts of macronutrients and the circadian clock on obesity have been reported, the interactions between macronutrient distribution and circadian genes are unclear. The aim of this study was to explore macronutrient intake patterns in the Korean population and associations between the patterns and circadian gene variants and obesity. After applying the criteria, 5343 subjects (51.6% male, mean age 49.4 ± 7.3 years) from the Korean Genome and Epidemiology Study data and nine variants in seven circadian genes were analyzed. We defined macronutrient intake patterns by tertiles of the fat to carbohydrate ratio (FC). The very low FC (VLFC) was associated with a higher risk of obesity than the optimal FC (OFC). After stratification by the genotypes of nine variants, the obesity risk according to the patterns differed by the variants. In the female VLFC, the major homozygous allele of CLOCK rs11932595 and CRY1 rs3741892 had a higher abdominal obesity risk than those in the OFC. The GG genotype of PER2 rs2304672 in the VLFC showed greater risks for obesity and abdominal obesity. In conclusion, these findings suggest that macronutrient intake patterns were associated with obesity susceptibility, and the associations were different depending on the circadian clock genotypes of the CLOCK, PER2, and CRY1 loci.
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Marlow, Victoria L., Andreas F. Haag, Hajime Kobayashi, Vivien Fletcher, Marco Scocchi, Graham C. Walker e Gail P. Ferguson. "Essential Role for the BacA Protein in the Uptake of a Truncated Eukaryotic Peptide in Sinorhizobium meliloti". Journal of Bacteriology 191, n.º 5 (12 de dezembro de 2008): 1519–27. http://dx.doi.org/10.1128/jb.01661-08.
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ABSTRACT The inner membrane BacA protein is essential for the establishment of chronic intracellular infections by Sinorhizobium meliloti and Brucella abortus within plant and mammalian hosts, respectively. In their free-living state, S. meliloti and B. abortus mutants lacking BacA have reductions in their outer membrane lipid A very-long-chain fatty acid (VLCFA) contents and exhibit low-level resistance to the glycopeptide bleomycin in comparison to their respective parent strains. In this paper we investigate the hypothesis that BacA is involved in peptide uptake in S. meliloti. We determined that an S. meliloti ΔbacA mutant is completely resistant to a truncated form of the eukaryotic peptide Bac7, Bac7(1-16), and this phenotype appears to be independent of its lipid A alteration. Subsequently, we discovered that BacA and/or Escherichia coli SbmA is essential for fluorescently labeled Bac7(1-16) uptake in S. meliloti. Given that there are hundreds of root nodule-specific peptides within the legume host, our data suggest that BacA-mediated peptide uptake could play a central role in the chronic infection process of S. meliloti. However, since we determined that two symbiotically defective S. meliloti bacA site-directed mutants (with the Q193G and R389G mutations, respectively) with known reductions in their lipid A VLCFA contents are still capable of peptide uptake, these findings suggest that BacA-dependent peptide uptake cannot fully account for the essential role of BacA in the legume symbiosis. Further, they provide evidence that the BacA function that leads to the S. meliloti lipid A VLCFA modification plays a key role in the chronic infection of legumes.
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Song, Jinsoo, Yeon-Ho Kang, Sik Yoon, Churl-Hong Chun e Eun-Jung Jin. "HIF-1α:CRAT:miR-144-3p axis dysregulation promotes osteoarthritis chondrocyte apoptosis and VLCFA accumulation". Oncotarget 8, n.º 41 (1 de setembro de 2017): 69351–61. http://dx.doi.org/10.18632/oncotarget.20615.
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Doria, Margaux, Thomas Nury, Dominique Delmas, Thibault Moreau, Gérard Lizard e Anne Vejux. "Protective function of autophagy during VLCFA-induced cytotoxicity in a neurodegenerative cell model". Free Radical Biology and Medicine 137 (junho de 2019): 46–58. http://dx.doi.org/10.1016/j.freeradbiomed.2019.04.016.
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Gong, Yi, Fiza Laheji, Anna Berenson, April Qian, Sang-O. Park, Rene Kok, Martin Selig et al. "Peroxisome Metabolism Contributes to PIEZO2-Mediated Mechanical Allodynia". Cells 11, n.º 11 (4 de junho de 2022): 1842. http://dx.doi.org/10.3390/cells11111842.
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Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, Abcd1−/y mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
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Binczek, Erika, Britta Jenke, Barbara Holz, Robert Heinz Günter, Mario Thevis e Wilhelm Stoffel. "Obesity resistance of the stearoyl-CoA desaturase-deficient (scd1 -/-) mouse results from disruption of the epidermal lipid barrier and adaptive thermoregulation". Biological Chemistry 388, n.º 4 (1 de abril de 2007): 405–18. http://dx.doi.org/10.1515/bc.2007.046.
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Abstract Targeted deletion of the stearoyl-CoA desaturase 1 gene (scd1) in mouse causes obesity resistance and a severe skin phenotype. Here, we demonstrate that SCD1 deficiency disrupts the epidermal lipid barrier and leads to uncontrolled transepidermal water loss, breakdown of adaptive thermoregulation and cold resistance, as well as a metabolic wasting syndrome. The loss of ω-hydroxylated very long-chain fatty acids (VLCFA) and ceramides substituted with ω-hydroxylated VLCFA covalently linked to corneocyte surface proteins leads to the disruption of the epidermal lipid barrier in scd1 -/- mutants. Artificial occlusion of the skin by topical lipid application largely reconstituted the epidermal barrier and also reversed dysregulation of thermogenesis and cold resistance, as well as the metabolic disturbances. Interestingly, SCD1 deficiency abolished expression of the key transcription factor Lef1, which is essential for interfollicular epidermis, sebaceous glands, and hair follicle development. Finally, the occurrence of SCD1 and a newly described hSCD5 (ACOD4) gene in humans suggests that the scd1 -/- mouse mutant might be a valuable animal model for the study of human skin diseases associated with epidermal barrier defects.
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Song, Jinsoo, Yeon-Ho Kang, Sik Yoon, Churl-Hong Chun e Eun-Jung Jin. "Correction: HIF-1α:CRAT:miR-144-3p axis dysregulation promotes osteoarthritis chondrocyte apoptosis and VLCFA accumulation". Oncotarget 10, n.º 44 (16 de julho de 2019): 4609–10. http://dx.doi.org/10.18632/oncotarget.27091.
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Clayton, P. T. "Clinical consequences of defects in peroxisomal β-oxidation". Biochemical Society Transactions 29, n.º 2 (1 de maio de 2001): 298–305. http://dx.doi.org/10.1042/bst0290298.
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The disorders of peroxisomal β-oxidation, which have been well characterised at the molecular level, include defects of acyl-CoA oxidase, defects of the D-bifunctional protein (D-BP) (including specific defects of its enoyl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase components), defects of the very-long-chain fatty acid (VLCFA)-CoA importer [X-linked adrenoleukodystrophy (ALD)] and α-methylacyl-CoA racemase deficiency. A survey of the clinical consequences of these defects indicates that defects in the acyl-CoA oxidase and D-BP can produce neonatal hypotonia, seizures in early infancy, retinopathy and progressive neurological dysfunction with leukodystrophy on imaging. Defects in the VLCFA-CoA importer and in the racemase do not produce disease until a long time after the neonatal period. However, again the clinical picture is dominated by neurological disease: impaired cognitive function with leukodystrophy in childhood X-linked ALD and retinopathy and neuropathy in racemase deficiency. It is difficult to escape the conclusion that defective peroxisomal β-oxidation has effects (such as impaired neuronal migration in the developing brain), which are more serious than those produced by the accumulation of substrates (VLCFAs, pristanic acid) alone.
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Fourcade, Stéphane, Montserrat Ruiz, Carme Camps, Agatha Schlüter, Sander M. Houten, Petra A. W. Mooyer, Teresa Pàmpols et al. "A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis". American Journal of Physiology-Endocrinology and Metabolism 296, n.º 1 (janeiro de 2009): E211—E221. http://dx.doi.org/10.1152/ajpendo.90736.2008.
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Peroxisomes are essential organelles exerting key functions in fatty acid metabolism such as the degradation of very long-chain fatty acids (VLCFAs). VLCFAs accumulate in X-adrenoleukodystrophy (X-ALD), a disease caused by deficiency of the Abcd1 peroxisomal transporter. Its closest homologue, Abcd2, exhibits a high degree of functional redundancy on the catabolism of VLCFA, being able to prevent X-ALD-related neurodegeneration in the mouse. In the search for specific roles of Abcd2, we screened fatty acid profiles in organs and primary neurons of mutant knockout mice lacking Abcd2 in basal conditions and under dietary challenges. Our results indicate that ABCD2 plays a role in the degradation of long-chain saturated and ω9-monounsaturated fatty acids and in the synthesis of docosahexanoic acid (DHA). Also, we demonstrated a defective VLCFA β-oxidation ex vivo in brain slices of Abcd1 and Abcd2 knockouts, using radiolabeled hexacosanoic acid and the precursor of DHA as substrates. As DHA levels are inversely correlated with the incidence of Alzheimer's and several degenerative conditions, we suggest that ABCD2 may act as modulator/modifier gene and therapeutic target in rare and common human disorders.