Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons leading to muscle paralysis and death. While a link between dysregulated lipid metabolism and ...ALS has been proposed, lipidome alterations involved in disease progression are still understudied. Using a rodent model of ALS overexpressing mutant human Cu/Zn-superoxide dismutase gene (SOD1-G93A), we performed a comparative lipidomic analysis in motor cortex and spinal cord tissues of SOD1-G93A and WT rats at asymptomatic (~70 days) and symptomatic stages (~120 days). Interestingly, lipidome alterations in motor cortex were mostly related to age than ALS. In contrast, drastic changes were observed in spinal cord of SOD1-G93A 120d group, including decreased levels of cardiolipin and a 6-fold increase in several cholesteryl esters linked to polyunsaturated fatty acids. Consistent with previous studies, our findings suggest abnormal mitochondria in motor neurons and lipid droplets accumulation in aberrant astrocytes. Although the mechanism leading to cholesteryl esters accumulation remains to be established, we postulate a hypothetical model based on neuroprotection of polyunsaturated fatty acids into lipid droplets in response to increased oxidative stress. Implicated in the pathology of other neurodegenerative diseases, cholesteryl esters appear as attractive targets for further investigations.
The methane-rich, hydrothermally heated sediments of the Guaymas Basin are inhabited by thermophilic microorganisms, including anaerobic methane-oxidizing archaea (mainly ANME-1) and sulfate-reducing ...bacteria (e.g., HotSeep-1 cluster). We studied the microbial carbon flow in ANME-1/ HotSeep-1 enrichments in stable-isotope–probing experiments with and without methane. The relative incorporation of ¹³C from either dissolved inorganic carbon or methane into lipids revealed that methane-oxidizing archaea assimilated primarily inorganic carbon. This assimilation is strongly accelerated in the presence of methane. Experiments with simultaneous amendments of both ¹³C-labeled dissolved inorganic carbon and deuterated water provided further insights into production rates of individual lipids derived from members of the methane-oxidizing community as well as their carbon sources used for lipid biosynthesis. In the presence of methane, all prominent lipids carried a dual isotopic signal indicative of their origin from primarily autotrophic microbes. In the absence of methane, archaeal lipid production ceased and bacterial lipid production dropped by 90%; the lipids produced by the residual fraction of the metabolically active bacterial community predominantly carried a heterotrophic signal. Collectively our results strongly suggest that the studied ANME-1 archaea oxidize methane but assimilate inorganic carbon and should thus be classified as methane-oxidizing chemoorganoautotrophs.
The 2015-2016 Zika virus (ZIKV) outbreak in Brazil was remarkably linked to the incidence of microcephaly and other deleterious clinical manifestations, including eye abnormalities, in newborns. It ...is known that ZIKV targets the placenta, triggering an inflammatory profile that may cause placental insufficiency. Transplacental lipid transport is delicately regulated during pregnancy and deficiency on the delivery of lipids such as arachidonic and docosahexaenoic acids may lead to deficits in both brain and retina during fetal development. Here, plasma lipidome profiles of ZIKV exposed microcephalic and normocephalic newborns were compared to non-infected controls. Our results reveal major alterations in circulating lipids from both ZIKV exposed newborns with and without microcephaly relative to controls. In newborns with microcephaly, the plasma concentrations of hydroxyoctadecadienoic acid (HODE), primarily as 13-HODE isomer, derived from linoleic acid were higher as compared to normocephalic ZIKV exposed newborns and controls. Total HODE concentrations were also positively associated with levels of other oxidized lipids and several circulating free fatty acids in newborns, indicating a possible plasma lipidome signature of microcephaly. Moreover, higher concentrations of lysophosphatidylcholine in ZIKV exposed normocephalic newborns relative to controls suggest a potential disruption of polyunsaturated fatty acids transport across the blood-brain barrier of fetuses. The latter data is particularly important given the neurocognitive and neurodevelopmental abnormalities observed in follow-up studies involving children with antenatal ZIKV exposure, but normocephalic at birth. Taken together, our data reveal that plasma lipidome alterations associated with antenatal exposure to ZIKV could contribute to identification and monitoring of the wide spectrum of clinical phenotypes at birth and further, during childhood.
The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients, and ...dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export, and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.
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•Integrated lipidomic & transcriptomic study of the oxygen-induced retinopathy (OIR)•OIR increases triglyceride/cholesteryl ester synthesis for lipid droplet formation•Cholesterol import/export pathways are increased in retinopathy•OIR increases retinal n-9 lipids (mead acid), a possible marker of disease severity
Molecular mechanism of behavior; Metabolomics
Cardiolipin is the signature phospholipid of the mitochondrial inner membrane. It participates in shaping the inner membrane as well as in modulating the activity of many membrane-bound proteins. The ...acyl chain composition of cardiolipin is finely tuned post-biosynthesis depending on the surrounding phospholipids to produce mature or unsaturated cardiolipin. However, experimental evidence showing that immature and mature cardiolipin are functionally equivalents for mitochondria poses doubts on the relevance of cardiolipin remodeling. In this work, we studied the role of cardiolipin acyl chain composition in mitochondrial bioenergetics, including a detailed bioenergetic profile of yeast mitochondria. Cardiolipin acyl chains were modified by genetic and nutritional manipulation. We found that both the bioenergetic efficiency and osmotic stability of mitochondria are dependent on the unsaturation level of cardiolipin acyl chains. It is proposed that cardiolipin remodeling and, consequently, mature cardiolipins play an important role in mitochondrial inner membrane integrity and functionality.
•External linoleic acid is incorporated into phospholipids.•Polyunsaturated cardiolipin improves the oxidative capacity of mitochondria.•Mitochondrial osmotic stability enhances when mitochondria is enriched in unsaturated cardiolipins.•A high proportion of saturated cardiolipins in mitochondria led to osmotic instability.
The Carnitine Palmitoyltranferase I (CPT1) catalyzes the rate-limiting step of long-chain fatty acid (LCFA) mitochondrial β-oxidation. The enzyme promotes the conjugation of LCFA with l-carnitine, ...which allows LCFA to enter the mitochondria matrix. The structural features involved in CPT1 and LCFA-CoA interactions have not been fully elucidated, mainly due to the absence of CPT1 crystallographic data. Previous studies reported important residues (Lys556, Lys560, and Lys561) crucial to the CPT1 mechanism. Nonetheless, these studies have not explored the LCFA bindings. Using molecular modeling strategies, we aimed to understand the conformational changes in CPT1 structure induced by LCFA-CoA. For this purpose, a tridimensional CPT1A model was built by homology modeling using CRAT protein (PBD:1t7q, resolution 1.8 Å) as a template. We simulated the CPT1 structure in the presence and absence of LCFA-CoA by molecular dynamics (MD). By applying a principal component analysis (PCA), two states of apostructure CPT1 based on CoA-Loop (688–711) were observed. In contrast, just one state was evidenced along with smaller conformational subspaces in ligand-complexed simulations using LCFA-CoA. The CoA moiety of ligands interacts with charged residues, namely Lys560, Lys556, Arg563, and Arg645. The frequency of interactions observed for each of these residues is <60% of simulation time, suggesting a dynamic profile of interactions in synergy with long-chain carbon interactions over α-I (478–492). Collectively, these features may be associated with the catalytic conformation of LCFA-CoA to CPT1a. Further calculations of free-energy for different fatty acids, such as alpha-linolenic (ALA), gamma-linolenic (GLA), and arachidonic (ARA) acids, yielded energy values ranging from −76.9 ± 15.9 to −68.5 ± 10.0 kcal mol−1. In conclusion, the present structural model and simulations provide molecular-level insights into LCFA-CoA and CPT1a interactions. These findings may help to further knowledge on the conformational changes of CPT1a induced by LCFA-CoA derivates.
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•The CPT1 catalyzes the rate limiting step of β-Oxidation.•The interactions of CoA moiety were stabilized by charged residues (Lys560, Lys556, Arg563, and Arg645).•The CPT1 tridimensional model showed affinity of ligands in order alpha-linolenic > gamma-linolenic > arachidonic.•The PCA analysis showed different clusters of conformational distribution.•The CoA-Loop flexibility is affected by ligand binding.
Postprandial lipemia consists of changes in concentrations and composition of plasma lipids after food intake, commonly presented as increased levels of triglyceride-rich lipoproteins. Postprandial ...hypertriglyceridemia may also affect high-density lipoprotein (HDL) structure and function, resulting in a net decrease in HDL concentrations. Elevated triglycerides (TG) and reduced HDL levels have been positively associated with risk of cardiovascular diseases development. Here, we investigated the plasma lipidome composition of 12 clinically healthy, nonobese and young women in response to an acute high-caloric (1135 kcal) and high-fat (64 g) breakfast meal. For this purpose, we employed a detailed untargeted mass spectrometry-based lipidomic approach and data was obtained at four sampling points: fasting and 1, 3 and 5 h postprandial. Analysis of variance revealed 73 significantly altered lipid species between all sampling points. Nonetheless, two divergent subgroups have emerged at 5 h postprandial as a function of differential plasma lipidome responses, and were thereby designated slow and fast TG metabolizers. Late responses by slow TG metabolizers were associated with increased concentrations of several species of TG and phosphatidylinositol (PI). Lipidomic analysis of lipoprotein fractions at 5 h postprandial revealed higher TG and PI concentrations in HDL from slow relative to fast TG metabolizers, but not in apoB-containing fraction. These data indicate that modulations in HDL lipidome during prolonged postprandial lipemia may potentially impact HDL functions. A comprehensive characterization of plasma lipidome responses to acute metabolic challenges may contribute to a better understanding of diet/lifestyle regulation in the metabolism of lipid and glucose.
In the yeast Saccharomyces cerevisiae, the absence of the pseudouridine synthase Pus3/Deg1, which modifies tRNA positions 38 and 39, results in increased lipid droplet (LD) content and translational ...defects. In addition, starvation‐like transcriptome alterations and induced protein aggregation were observed. In this study, we show that the deg1 mutant increases specific misreading errors. This could lead to altered expression of the main regulators of neutral lipid synthesis which are the acetyl‐CoA carboxylase (Acc1), an enzyme that catalyzes a key step in fatty acid synthesis, and its regulator, the Snf1/AMPK kinase. We demonstrate that upregulation of the neutral lipid content of LD in the deg1 mutant is achieved by a mechanism operating in parallel to the known Snf1/AMPK kinase‐dependent phosphoregulation of Acc1. While in wild‐type cells removal of the regulatory phosphorylation site (Ser‐1157) in Acc1 results in strong upregulation of triacylglycerol (TG), but not steryl esters (SE), the deg1 mutation more specifically upregulates SE levels. In order to elucidate if other lipid species are affected, we compared the lipidomes of wild type and deg1 mutants, revealing multiple altered lipid species. In particular, in the exponential phase of growth, the deg1 mutant shows a reduction in the pool of phospholipids, indicating a compromised capacity to mobilize acyl‐CoA from storage lipids. We conclude that Deg1 plays a key role in the coordination of lipid storage and mobilization, which in turn influences lipid homeostasis. The lipidomic effects in the deg1 mutant may be indirect outcomes of the activation of various stress responses resulting from protein aggregation.
The tRNA modifier Deg1/Pus3 introduces pseudouridine at specific positions in tRNA, and apart from direct effects on decoding, it affects the remodeling of the lipidome which normally occurs when stationary cells enter a new growth phase. Lipidome analysis reveals that the storage lipid steryl ester fails to be mobilized resulting in phospholipid depletion.
Two commercial exogenous pulmonary surfactants, Curosurf and Survanta, are investigated. Their thermotropic behavior and associated structural changes for the samples in bulk are characterized and ...described. For Survanta, the obtained results of differential scanning calorimetry showed a thermogram with three peaks on heating and only a single peak on cooling. Curosurf on the other hand, presents calorimetric thermograms with only one peak in both the heating and cooling scans. This distinct thermotropic behavior between the two pulmonary surfactants, a consequence of their particular compositions, is associated with structural changes that were evaluated by simultaneous small- and wide-angle X-ray scattering experiments with in situ temperature variation. Interestingly, for temperatures below ∼35 °C for Curosurf and ∼53 °C for Survanta, the scattering data indicated the coexistence of two lamellar phases with different carbon chain organizations. For temperatures above these limits, the coexistence of phases disappears, giving rise to a fluid phase in both pulmonary surfactants, with multilamelar vesicles for Curosurf and unilamellar vesicles for Survanta. This process is quasi-reversible under cooling, and advanced data analysis for the scattering data indicated differences in the structural and elastic properties of the pulmonary surfactants. The detailed and systematic investigation shown in this work expands on the knowledge of the structure and thermodynamic behavior of Curosurf and Survanta, being relevant from both physiological and biophysical perspectives and also providing a basis for further studies on other types of pulmonary surfactants.
Familial hypercholesterolemia (FH) is a disorder of lipid metabolism that causes elevated low-density lipoprotein cholesterol (LDL-c) and increased premature atherosclerosis risk. Statins inhibit ...endogenous cholesterol biosynthesis, which reduces LDL-c plasma levels and prevent from cardiovascular events. This study aimed to explore the effects of statin treatment on serum lipidomic profile and to identify biomarkers of response in subjects with FH. Seventeen adult FH patients underwent a 6-week washout followed by 4-week treatment with atorvastatin (80 mg/day) or rosuvastatin (40 mg/day). LDL-c response was considered good (40–70 % reduction, n = 9) or poor (3–33 % reduction, n = 8). Serum lipidomic profile was analyzed by ultra-high-performance liquid chromatography combined with electrospray ionization tandem time-of-flight mass spectrometry, and data were analyzed using MetaboAnalyst v5.0. Lipidomic analysis identified 353 lipids grouped into 16 classes. Statin treatment reduced drastically 8 of 13 lipid classes, generating a characteristic lipidomic profile with a significant contribution of phosphatidylinositols (PI) 16:0/18:2, 18:0/18:1 and 18:0/18:2; and triacylglycerols (TAG) 18:2x2/18:3, 18:1/18:2/18:3, 16:1/18:2x2, 16:1/18:2/18:3 and 16:1/18:2/Arachidonic acid (p-adjusted <0.05). Biomarker analysis implemented in MetaboAnalyst subsequently identified PI 16:1/18:0, 16:0/18:2 and 18:0/18:2 as predictors of statin response with and receiver operating characteristic (ROC) areas under the curve of 0.98, 0.94 and 0.91, respectively. In conclusion, statins extensively modulate the overall serum lipid composition of FH individuals and these findings suggest that phosphatidyl-inositol molecules are potential predictive biomarkers of statin response.
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•Statins change serum lipidomic profile in Familial Hypercholesterolemia patients.•Posphatidyl-inositol and triacylglycerol are key in posttreatment discriminant analysis.•Posphatidyl-inositol molecules are predictive biomarkers of statin response.
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