Less Lipid, More Commitment.

Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci et al., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment.

Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum.

Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.

Metabolism of host lysophosphatidylcholine in Plasmodium falciparum-infected erythrocytes.

The human malaria parasite Plasmodium falciparum requires exogenous fatty acids to support its growth during the pathogenic, asexual erythrocytic stage. Host serum lysophosphatidylcholine (LPC) is a significant fatty acid source, yet the metabolic processes responsible for the liberation of free fatty acids from exogenous LPC are unknown. Using an assay for LPC hydrolysis in P. falciparum-infected erythrocytes, we have identified small-molecule inhibitors of key in situ lysophospholipase activities. Competitive activity-based profiling and generation of a panel of single-to-quadruple knockout parasite lines revealed that two enzymes of the serine hydrolase superfamily, termed exported lipase (XL) 2 and exported lipase homolog (XLH) 4, constitute the dominant lysophospholipase activities in parasite-infected erythrocytes. The parasite ensures efficient exogenous LPC hydrolysis by directing these two enzymes to distinct locations: XL2 is exported to the erythrocyte, while XLH4 is retained within the parasite. While XL2 and XLH4 were individually dispensable with little effect on LPC hydrolysis in situ, loss of both enzymes resulted in a strong reduction in fatty acid scavenging from LPC, hyperproduction of phosphatidylcholine, and an enhanced sensitivity to LPC toxicity. Notably, growth of XL/XLH-deficient parasites was severely impaired when cultured in media containing LPC as the sole exogenous fatty acid source. Furthermore, when XL2 and XLH4 activities were ablated by genetic or pharmacologic means, parasites were unable to proliferate in human serum, a physiologically relevant fatty acid source, revealing the essentiality of LPC hydrolysis in the host environment and its potential as a target for anti-malarial therapy.

Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport.

Major Facilitator Superfamily Domain containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine (LPC) transporter expressed at the blood-brain barrier that constitutes the main pathway by which the brain obtains omega-3 fatty acids, such as docosahexanoic acid. Mfsd2a deficiency in humans results in severe microcephaly, underscoring the importance of LPC transport by Mfsd2a for brain development. Biochemical studies and recent cryo-electron microscopy (cryo-EM) structures of Mfsd2a bound to LPC suggest that Mfsd2a transports LPC via an alternating access mechanism between outward-facing and inward-facing conformational states in which the LPC inverts during transport between the outer and inner leaflet of a membrane. However, direct biochemical evidence of flippase activity by Mfsd2a has not been demonstrated and it is not understood how Mfsd2a could invert LPC between the outer and inner leaflet of the membrane in a sodium-dependent manner. Here, we established a unique in vitro assay using recombinant Mfsd2a reconstituted in liposomes that exploits the ability of Mfsd2a to transport lysophosphatidylserine (LPS) coupled with a small molecule LPS binding fluorophore that allowed for monitoring of directional flipping of the LPS headgroup from the outer to the inner liposome membrane. Using this assay, we demonstrate that Mfsd2a flips LPS from the outer to the inner leaflet of a membrane bilayer in a sodium-dependent manner. Furthermore, using cryo-EM structures as guides together with mutagenesis and a cell-based transport assay, we identify amino acid residues important for Mfsd2a activity that likely constitute substrate interaction domains. These studies provide direct biochemical evidence that Mfsd2a functions as a lysolipid flippase.

Neutral lysophosphatidylcholine mediates α-synuclein-induced synaptic vesicle clustering.

α-synuclein (α-Syn) is a presynaptic protein that is involved in Parkinson's and other neurodegenerative diseases and binds to negatively charged phospholipids. Previously, we reported that α-Syn clusters synthetic proteoliposomes that mimic synaptic vesicles. This vesicle-clustering activity depends on a specific interaction of α-Syn with anionic phospholipids. Here, we report that α-Syn surprisingly also interacts with the neutral phospholipid lysophosphatidylcholine (lysoPC). Even in the absence of anionic lipids, lysoPC facilitates α-Syn-induced vesicle clustering but has no effect on Ca2+-triggered fusion in a single vesicle-vesicle fusion assay. The A30P mutant of α-Syn that causes familial Parkinson disease has a reduced affinity to lysoPC and does not induce vesicle clustering. Taken together, the α-Syn-lysoPC interaction may play a role in α-Syn function.

Dysregulated Cholinergic Signaling Inhibits Oligodendrocyte Maturation Following Demyelination.

Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS.

Functional determinants of lysophospholipid- and voltage-dependent regulation of TRPC5 channel.

Lysophosphatidylcholine (LPC) is a bioactive lipid present at high concentrations in inflamed and injured tissues where it contributes to the initiation and maintenance of pain. One of its important molecular effectors is the transient receptor potential canonical 5 (TRPC5), but the explicit mechanism of the activation is unknown. Using electrophysiology, mutagenesis and molecular dynamics simulations, we show that LPC-induced activation of TRPC5 is modulated by xanthine ligands and depolarizing voltage, and involves conserved residues within the lateral fenestration of the pore domain. Replacement of W577 with alanine (W577A) rendered the channel insensitive to strong depolarizing voltage, but LPC still activated this mutant at highly depolarizing potentials. Substitution of G606 located directly opposite position 577 with tryptophan rescued the sensitivity of W577A to depolarization. Molecular simulations showed that depolarization widens the lower gate of the channel and this conformational change is prevented by the W577A mutation or removal of resident lipids. We propose a gating scheme in which depolarizing voltage and lipid-pore helix interactions act together to promote TRPC5 channel opening.

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.

The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.

Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1.

Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows: LPC O-16:0, LPC O-18:1, and LPC O-18:0. However, the levels of PAF 16:0, PAF 18:1, and PAF 18:0 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-ß-cyclodextrin (HPßCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-16:0 and LPC O-18:1 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPßCD treatment. The fold increases in CSF LPC O-16:0 and LPC O-18:1 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-16:0 and LPC O-18:1, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients.

Plasma C24:0- and C26:0-lysophosphatidylcholines are reliable biomarkers for the diagnosis of peroxisomal ß-oxidation disorders.

The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's time-consuming nature and limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS) has successfully been implemented in certain newborn screening programs to diagnose X-linked adrenoleukodystrophy (ALD). However, the diagnostic potential of very long-chain LPCs concentrations in plasma remains poorly understood. This study sought to evaluate the diagnostic performance of C26:0-LPC and other very long-chain LPCs, comparing them to VLCFA analysis in plasma. The study, which included 330 individuals affected by a peroxisomal ß-oxidation deficiency and 407 control individuals, revealed that C26:0- and C24:0-LPC concentrations demonstrated the highest diagnostic accuracy (98.8% and 98.4%, respectively), outperforming VLCFA when C26:0/C22:0 and C24:0/C22:0 ratios were combined (98.1%). Combining C24:0- and C26:0-LPC gave the highest sensitivity (99.7%), with ALD females exhibiting notably higher sensitivity compared with the VLCFA ratio combination (98.7% vs. 93.5%, respectively). In contrast, C22:0-LPC exhibited suboptimal performance, primarily due to its low sensitivity (75%), but we identified a potential use to help distinguish between ALD and Zellweger spectrum disorders. In summary, MS/MS analysis of plasma C24:0- and C26:0-LPC concentrations represents a rapid and straightforward approach to diagnose PDs, demonstrating superior diagnostic accuracy, particularly in ALD females, compared with conventional VLCFA biomarkers. We strongly recommend integrating very-long chain LPC plasma analysis in the diagnostic evaluation of individuals suspected of having a PD.

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Arabidopsis PROTODERMAL FACTOR2 binds lysophosphatidylcholines and transcriptionally regulates phospholipid metabolism.

Plant homeodomain leucine zipper IV (HD-Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear. Here we used tandem affinity purification from Arabidopsis cell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START-dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding. We additionally found that PDF2 acts as a transcriptional regulator of phospholipid- and phosphate (Pi) starvation-related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered in pdf2 mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity. We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression.

Classifying patients with psoriatic arthritis according to their disease activity status using serum metabolites and machine learning.

INTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis, affecting approximately a quarter of patients with psoriasis. Accurate assessment of disease activity is difficult. There are currently no clinically validated biomarkers to stratify PsA patients based on their disease activity, which is important for improving clinical management. OBJECTIVES: To identify metabolites capable of classifying patients with PsA according to their disease activity. METHODS: An in-house solid-phase microextraction (SPME)-liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for lipid analysis was used to analyze serum samples obtained from patients classified as having low (n = 134), moderate (n = 134) or high (n = 104) disease activity, based on psoriatic arthritis disease activity scores (PASDAS). Metabolite data were analyzed using eight machine learning methods to predict disease activity levels. Top performing methods were selected based on area under the curve (AUC) and significance. RESULTS: The best model for predicting high disease activity from low disease activity achieved AUC 0.818. The best model for predicting high disease activity from moderate disease activity achieved AUC 0.74. The best model for classifying low disease activity from moderate and high disease activity achieved AUC 0.765. Compounds confirmed by MS/MS validation included metabolites from diverse compound classes such as sphingolipids, phosphatidylcholines and carboxylic acids. CONCLUSION: Several lipids and other metabolites when combined in classifying models predict high disease activity from both low and moderate disease activity. Lipids of key interest included lysophosphatidylcholine and sphingomyelin. Quantitative MS assays based on selected reaction monitoring, are required to quantify the candidate biomarkers identified.

Exploration of circulating metabolic signature of erythrodermic psoriasis based on LC-MS metabolomics.

Erythrodermic psoriasis (EP) is a rare and life-threatening disease, the pathogenesis of which remains to be largely unknown. Metabolomics analysis can provide global information on disease pathophysiology, candidate biomarkers, and potential intervention strategies. To gain a better understanding of the mechanisms of EP and explore the serum metabolic signature of EP, we conducted an untargeted metabolomics analysis from 20 EP patients and 20 healthy controls. Furthermore, targeted metabolomics for focused metabolites were identified in the serum samples of 30 EP patients and 30 psoriasis vulgaris (PsV) patients. In the untargeted analysis, a total of 2992 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant difference between groups. After screening, 98 metabolites were found to be significantly dysregulated in EP, including 67 down-regulated and 31 up-regulated. EP patients had lower levels of L-tryptophan, L-isoleucine, retinol, lysophosphatidylcholine (LPC), and higher levels of betaine and uric acid. KEGG analysis showed differential metabolites were enriched in amino acid metabolism and glycerophospholipid metabolism. The targeted metabolomics showed lower L-tryptophan in EP than PsV with significant difference and L-tryptophan levels were negatively correlated with the PASI scores. The serum metabolic signature of EP was discovered. Amino acid and glycerophospholipid metabolism were dysregulated in EP. The metabolite differences provide clues for pathogenesis of EP and they may provide insights for therapeutic interventions.

Lysophosphatidylcholine induces oxidative stress and calcium-mediated cell death in human blood platelets.

Platelets are essential component of circulation that plays a major role in hemostasis and thrombosis. During activation and its demise, platelets release platelet-derived microvesicles, with lysophosphatidylcholine (LPC) being a prominent component in their lipid composition. LPC, an oxidized low-density lipoprotein, is involved in cellular metabolism, but its higher level is implicated in pathologies like atherosclerosis, diabetes, and inflammatory disorders. Despite this, its impact on platelet function remains relatively unexplored. To address this, we studied LPC's effects on washed human platelets. A multimode plate reader was employed to measure reactive oxygen species and intracellular calcium using H2DCF-DA and Fluo-4-AM, respectively. Flow cytometry was utilized to measure phosphatidylserine expression, mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) formation using FITC-Annexin V, JC-1, and CoCl2/calcein-AM, respectively. Additionally, platelet morphology and its ultrastructure were observed via phase contrast and electron microscopy. Sonoclot and light transmission aggregometry were employed to examine fibrin formation and platelet aggregation, respectively. The findings demonstrate that LPC induced oxidative stress and increased intracellular calcium in platelets, resulting in increased phosphatidylserine expression and reduced ΔΨm. LPC triggered caspase-independent platelet death and mPTP opening via cytosolic and mitochondrial calcium, along with microvesiculation and reduced platelet counts. LPC increased the platelet's size, adopting a balloon-shaped morphology, causing membrane fragmentation and releasing its cellular contents, while inducing a pro-coagulant phenotype with increased fibrin formation and reduced integrin αIIbß3 activation. Conclusively, this study reveals LPC-induced oxidative stress and calcium-mediated platelet death, necrotic in nature with pro-coagulant properties, potentially impacting inflammation and repair mechanisms during vascular injury.

Precise Metabolomics Defines Systemic Metabolic Dysregulation Distinct to Acute Myocardial Infarction Associated With Diabetes.

BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of death and disability. Diabetes is an important risk factor and a common comorbidity in AMI patients. The higher mortality risk of diabetes-AMI relative to nondiabetes-AMI indicates a need for specific treatment to improve clinical outcome. However, the global metabolic dysregulation of AMI complicated with diabetes is still unclear. We aim to systematically interrogate changes in the metabolic microenvironment immediate to AMI episodes in the absence or presence of diabetes. METHODS: In this work, quantitative metabolomics was used to investigate plasma metabolic differences between diabetes-AMI (n=59) and nondiabetes-AMI (n=59) patients. A diverse array of perturbed metabolic pathways involving carbohydrate metabolism, lipid metabolism, glycolysis, tricarboxylic acid cycle, and amino acid metabolism emerged. RESULTS: In all, our omics-oriented approach defined a metabolic signature of afflicted mitochondrial function aggravated by concurrent diabetes in AMI patients. In particular, our analyses uncovered N-lactoyl-phenylalanine and lysophosphatidylcholines as key functional metabolites that skewed the metabolic picture of diabetes-AMI relative to nondiabetes-AMI. N-lactoyl-phenylalanine was strongly associated with metabolic indicators reflective of mitochondrial overload and negatively correlated with HbA1c (glycosylated hemoglobin, type A1C) specifically in hyperglycemic AMI, suggestive of its central role in glucose utilization and mitochondrial energy production instrumental to the clinical outcome of diabetes-AMI. Reductions in lysophosphatidylcholines, which were negatively correlated with blood glucose and inflammatory markers, might further compromise glucose expenditure and aggravate inflammation leading to poorer prognosis in diabetes-AMI. CONCLUSIONS: As circulating metabolite levels are amenable to therapeutic intervention, such shifts in metabolic signatures provide new clues and potential therapeutic targets specific to the treatment of diabetes-AMI.

Lysophospholipase D activity on oral mucosa cells in whole mixed human saliva involves in production of bioactive lysophosphatidic acid from lysophosphatidylcholine.

We reported that lysophosphatidic acid (LPA) is present at 0.8 µM in mixed human saliva (MS). In this study, we examined the distribution, origin, and enzymatic generation pathways of LPA in MS. LPA was distributed in the medium and cell pellet fraction; a true level of soluble LPA in MS was about 150 nM. The soluble LPA was assumed to be generated by ecto-type lysophospholipase D on exfoliated cells in MS from LPC that originated mainly from the major salivary gland saliva. Our results with the albumin-back extraction procedures suggest that a significant pool of LPA is kept in the outer layer of the plasma membranes of detached oral mucosal cells. Such pool of LPA may contribute to wound healing in upper digestive organs including oral cavity. We obtained evidence that the choline-producing activity in MS was mainly due to Ca2+-activated lysophospholipase D activity of glycerophosphodiesterase 7.

Magnetization transfer ratio for assessing remyelination after transcranial ultrasound stimulation in the lysolecithin rat model of multiple sclerosis.

It has been shown that transcranial ultrasound stimulation (TUS) is capable of attenuating myelin loss and providing neuroprotection in animal models of brain disorders. In this study, we investigated the ability of TUS to promote remyelination in the lysolecithin (LPC)-induced local demyelination in the hippocampus. Demyelination was induced by the micro-injection of 1.5 µL LPC (1%) into the rat hippocampus and the treated group received daily TUS for 5 or 12 days. Magnetic resonance imaging techniques, including magnetization transfer ratio (MTR) and T2-weighted imaging, were used to longitudinally characterize the demyelination model. Furthermore, the therapeutic effects of TUS on LPC-induced demyelination were assessed by Luxol fast blue (LFB) staining. Our data revealed that reductions in MTR values observed during demyelination recover almost completely upon remyelination. The MTR values in demyelinated lesions were significantly higher in TUS-treated rats than in the LPC-only group after undergoing TUS. Form histological observation, TUS significantly reduced the size of demyelinated lesion 7 days after LPC administration. This study demonstrated that MTR was a sensitive and reproducible quantitative marker to assess remyelination process in vivo during TUS treatment. These findings might open new promising treatment strategies for demyelinating diseases such as multiple sclerosis.

Plasma metabolomic markers underlying skeletal muscle mitochondrial function relationships with cognition and motor function.

BACKGROUND: Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. METHODS: We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4 years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). RESULTS: The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. CONCLUSION: Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes.

Circulatory levels of lysophosphatidylcholine species in obese adolescents: Findings from cross-sectional and prospective lipidomics analyses.

BACKGROUND AND AIMS: Obesity has reached epidemic proportions, emphasizing the importance of reliable biomarkers for detecting early metabolic alterations and enabling early preventative interventions. However, our understanding of the molecular mechanisms and specific lipid species associated with childhood obesity remains limited. Therefore, the aim of this study was to investigate plasma lipidomic signatures as potential biomarkers for adolescent obesity. METHODS AND RESULTS: A total of 103 individuals comprising overweight/obese (n = 46) and normal weight (n = 57) were randomly chosen from the baseline ORANGE (Obesity Reduction and Noncommunicable Disease Awareness through Group Education) cohort, having been followed up for a median of 7.1 years. Plasma lipidomic profiling was performed using the UHPLC-HRMS method. We used three different models adjusted for clinical covariates to analyze the data. Clustering methods were used to define metabotypes, which allowed for the stratification of subjects into subgroups with similar clinical and metabolic profiles. We observed that lysophosphatidylcholine (LPC) species like LPC.16.0, LPC.18.3, LPC.18.1, and LPC.20.3 were significantly (p < 0.05) associated with baseline and follow-up BMI in adolescent obesity. The association of LPC species with BMI remained consistently significant even after adjusting for potential confounders. Moreover, applying metabotyping using hierarchical clustering provided insights into the metabolic heterogeneity within the normal and obese groups, distinguishing metabolically healthy individuals from those with unhealthy metabolic profiles. CONCLUSION: The specific LPC levels were found to be altered and increased in childhood obesity, particularly during the follow-up. These findings suggest that LPC species hold promise as potential biomarkers of obesity in adolescents, including healthy and unhealthy metabolic profiles.