Lipid Modulation Research Articles

Symmetry-adapted Markov state models of closing, opening, and desensitizing in α 7 nicotinic acetylcholine receptors.

α7 nicotinic acetylcholine receptors (nAChRs) are homopentameric ligand-gated ion channels with critical roles in the nervous system. Recent studies have resolved and functionally annotated closed, open, and desensitized states of these receptors, providing insight into ion permeation and lipid binding. However, the process by which α7 nAChRs transition between states remains unclear. To understand gating and lipid modulation, we generated two ensembles of molecular dynamics simulations of apo α7 nAChRs, with or without cholesterol. Using symmetry-adapted Markov state modeling, we developed a five-state gating model. Free energies recapitulated functional behavior, with the closed state dominating in absence of agonist. Open-to-nonconducting transition rates corresponded to experimental open durations. Cholesterol relatively stabilized the desensitized state, and reduced open-desensitized barriers. These results establish plausible asymmetric transition pathways between states, define lipid modulation effects on the α7 nAChR conformational cycle, and provide an ensemble of structural models applicable to rational design of lipidic pharmaceuticals.

A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid-responsive core calcium peroxide (CaO2) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe3+ based metal-organic framework structure, and biocompatible mPEG-DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O2) and hydrogen peroxide (H2O2) in the acidic TME, facilitating TCPP-based sonodynamic therapy and Fe3+-mediated Fenton-like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ) secretion to up-regulate the expression of long-chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.

Multi-omics analysis provides new insights into mechanism of didymin on non-alcoholic fatty liver disease in rats

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases accompanied by lipid and glucose metabolism disorder. Didymin has been reported to have various hepatoprotective effects, however, its potential effects and mechanisms on NAFLD remain unclear from the perspective of the whole. PurposeTo investigate the underlying mechanism of didymin against NAFLD using multi-omics technologies. MethodsRats were fed with a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by didymin treatment for 8 weeks. Next, biochemical analysis and histopathological examinations were performed to evaluate the effects of didymin. The key regulating pathways were predicted using transcriptomics, metabolomics and proteomics, and the target pathways were then verified by detecting the key genes/proteins using various experiments. ResultsDidymin markedly mitigated liver injury and excessive lipid droplet accretion. An integrative multi-omics analysis suggested that the PPAR signaling cascade and insulin signaling pathway might serve as pivotal mechanisms underlying the modulation of lipid and glucose homeostasis by didymin. Further dissection identified five pivotal genes (PPARα, PPARβ, FABP4, ANGPTL4, and PLIN2) and four genes (HK1, HK3, GCK, and PTPN1) as potential hubs within these pathways. Subsequent validation experiments, including qPCR and Western blot, demonstrated upregulated expression of PPARα and PPARβ, indicating the activation of the PPAR pathway by didymin. Concurrently, didymin appeared to modulate the insulin signaling pathway, as evidenced by the upregulated expression of HK1 and downregulated expression of PTPN1. Notably, the manipulation of PPARα, PPARβ, and PTPN1 expression in LO2 cells through silence or overexpression confirmed that didymin significantly reduced lipid accumulation, with its molecular targets likely being the PPAR and insulin pathways. ConclusionsOur findings demonstrate that didymin has a protective effect on NAFLD, and its underlying mechanism may be associated with the regulation of the PPAR and insulin signaling pathways.

Dietary modulation of lung lipids influences inflammatory responses to inhaled ozone

The pulmonary system represents a unique lipidomic environment as it contains cellular membrane-bound lipid species and a specialized reservoir of lipids in the airway epithelial lining fluid. As a major initial point of defense, airway lipids react to inhaled contaminants such as volatile organic compounds, oxides of nitrogen, or ozone (O3), creating lipokine signaling that is crucial for both the initiation and resolution of inflammation within the lung. Dietary modulation of eicosanoids has gained increased attention in recent years for improvements to cardiovascular health. The current study sought to examine how dietary supplementation with eicosanoid precursors (i.e, oils rich in saturated or polyunsaturated fatty acids) might alter the lung lipid composition and subsequently modify the inflammatory response to ozone inhalation. Our study demonstrated that mice fed a diet high in saturated fatty acids resulted in diet-specific changes to lung lipid profiles and increased cellular recruitment to the lung following ozone inhalation. Bioinformatic analysis revealed an ozone-dependent upregulation of several lipid species, including phosphoserine 37:5. Pathway analysis of lipid species revealed the process of lateral diffusion of lipids within membranes to be significantly altered due to ozone exposure. These results show promising data for influencing pulmonary lipidomic profiles via diet, which may provide a pragmatic therapeutic approach to protect against lung inflammation and damage following pulmonary insult.

Molecular Insights into Single Chain Lipid Modulation of Acid-Sensing Ion Channel 3.

Polyunsaturated fatty acids (PUFAs) and their analogs play a significant role in modulating the activity of diverse ion channels, and recent studies show that these lipids potentiate acid-sensing ion channels (ASICs), leading to increased activity. The potentiation of the channel stems from multiple gating changes, but the exact mechanism of these effects remains uncertain. We posit a mechanistic explanation for one of these changes in channel function, the increase in the maximal current, by applying a combination of electrophysiology and all-atom molecular dynamics simulations on the open-state hASIC3. Microsecond-scale simulations were performed on open-state hASIC3 in the absence and presence of a PUFA, docosahexaenoic acid (DHA), and a PUFA analog, N-arachidonyl glycine (AG). Intriguingly, our simulations in the absence of PUFA or PUFA analogs reveal that a tail from the membrane phospholipid POPC inserts itself into the pore of the channel through lateral fenestrations on the sides of the transmembrane segments, obstructing ion permeation through the channel. The binding of either DHA or AG prevented POPC from accessing the pore in our simulations, relieving the block of ionic conduction by phospholipids. Finally, we use the single-channel recording to show that DHA increases the amplitude of the single-channel currents in ASIC3, which is consistent with our hypothesis that PUFAs relieve the pore block of the channel induced by POPCs. Together, these findings offer a potential mechanistic explanation of how PUFAs modulate ASIC maximal current, revealing a novel mechanism of action for PUFA-induced modulation of ion channels.

LC/MS-Based Untargeted Lipidomics Reveals Lipid Signatures of Sarcopenia.

Sarcopenia, a multifactorial systemic disorder, has attracted extensive attention, yet its pathogenesis is not fully understood, partly due to limited research on the relationship between lipid metabolism abnormalities and sarcopenia. Lipidomics offers the possibility to explore this relationship. Our research utilized LC/MS-based nontargeted lipidomics to investigate the lipid profile changes as-sociated with sarcopenia, aiming to enhance understanding of its underlying mechanisms. The study included 40 sarcopenia patients and 40 control subjects matched 1:1 by sex and age. Plasma lipids were detected and quantified, with differential lipids identified through univariate and mul-tivariate statistical analyses. A weighted correlation network analysis (WGCNA) and MetaboAna-lyst were used to identify lipid modules related to the clinical traits of sarcopenia patients and to conduct pathway analysis, respectively. A total of 34 lipid subclasses and 1446 lipid molecules were detected. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified 80 differen-tial lipid molecules, including 38 phospholipids. Network analysis revealed that the brown module (encompassing phosphatidylglycerol (PG) lipids) and the yellow module (containing phosphati-dylcholine (PC), phosphatidylserine (PS), and sphingomyelin (SM) lipids) were closely associated with the clinical traits such as maximum grip strength and skeletal muscle mass (SMI). Pathway analysis highlighted the potential role of the glycerophospholipid metabolic pathway in lipid me-tabolism within the context of sarcopenia. These findings suggest a correlation between sarcopenia and lipid metabolism disturbances, providing valuable insights into the disease's underlying mechanisms and indicating potential avenues for further investigation.

Protective effects of spermidine levels against cardiovascular risk factors: An exploration of causality based on a bi-directional Mendelian randomization analysis

The study investigated the causal relationships between spermidine levels and CVD risk factors using a bi-directional MR approach. Employing genetic variants from extensive GWAS datasets as IVs, the study aimed to determine whether spermidine levels can influence CVD risk factors such as blood pressure, blood glucose, and lipid profiles, and vice versa. The findings suggest a protective role of elevated spermidine levels against hypertension, elevated blood glucose, and lipid profiles (LDL-C and HDL-C). Specifically, increased spermidine levels were significantly associated with lower risk of hypertension (IVW beta = -0.0013453913, p = 0.01597648) and suppression risk of elevated blood glucose (IVW beta = -0.08061330, p = 0.02450205). Additionally, there was a notable association with lipid modulation, showing a decrease in LDL-C (IVW beta = -0.01849161, p = 0.01086728) and an increase in HDL-C (IVW beta = 0.0044608332, P = 0.01760051). Conversely, the influence of CVD risk factors on spermidine levels was minimal, with the exception that elevated blood glucose levels resulted in reduced spermidine levels. (IVW beta = -0.06714391, P = 0.01096123). These results underline the potential of spermidine as a modifiable dietary target for the prevention and management of cardiovascular diseases. Further investigations are warranted to explore the underlying biological mechanisms and the applicability of these findings in broader and diverse populations.

Abstract Mo026: ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized MyH6-Cas9 mice (male and female) and CRISPR/Cas9 gene editing to generate a cardiac-specific Acly knockdown (AclyKD) mouse model. To assess how the loss of Acly impacts cardiac energy substrate metabolism, we conducted positron emission tomography in vivo and ex vivo stable isotope tracer labelling using working heart preparation. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics. Experimental data were integrated into computational modelling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Loss of ACL expression causes a left-ventricular cardiomyopathy by histology and echocardiography. FDG-PET/CT imaging in male and female mice demonstrated an increased glucose uptake and utilization in AclyKD mice, suggesting a substrate switch from fatty acid oxidation towards glucose. These findings were corroborated by stable isotope tracing, demonstrating that AclyKD suppresses fatty acid oxidation while enhancing lipid remodelling. AclyKD also reduced the efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. Computational flux analysis and integrative multi-omics analysis indicate that ACL activity supports lipid biosynthesis in the heart. Blocking mitochondrial isocitrate dehydrogenase or alpha-ketoglutarate dehydrogenase sensitized cardiomyocytes to ACL inhibition, and overexpressing cytosolic isocitrate dehydrogenase was sufficient to prevent citrate accumulation. Conclusions: Our work demonstrates a previously undescribed function of ACL as a regulator of cardiac energy substrate metabolism and lipid modulation.

Analysis of Longitudinal Patterns and Predictors of Medicine Use in Residential Aged Care Using Group-Based Trajectory Modeling: The "MEDTRAC-Cardiovascular" Longitudinal Cohort Study.

Cardiovascular diseases are the leading cause of death globally. Ensuring ongoing use of medicines-medication persistence-is crucial, yet no prior studies have examined this in residential aged care facilities (RACFs). We aimed to identify long-term trajectories of persistence with cardiovascular medicines and determine predictors of persistence trajectories. A longitudinal cohort study of 2837 newly admitted permanent residents from 30 RACFs in New South Wales, Australia. We monitored weekly exposure to six cardiovascular medicine classes-lipid modifiers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs), beta-blockers, diuretics, calcium channel blockers (CCB), and cardiac therapy-over 3 years. Group-based trajectory modeling was employed to determine persistence trajectories for each class. At baseline, 76.6% (n = 2172) received at least one cardiovascular medicine with 41.2% receiving lipid modifiers, 31.4% ACEI/ARBs, 30.2% beta-blockers, 24.4% diuretics, 18.7% CCBs, and 14.8% cardiac therapy. The model identified two persistence trajectories for CCBs and three trajectories for all other classes. Sustained high persistence rates ranged from 68.4% (ACEI/ARBs) to 79.8% (beta-blockers) while early decline in persistence and subsequent discontinuation rates ranged from 7.6% (cardiac therapy) to 25.3% (CCBs). Logistic regressions identified 11 predictors of a declining persistence across the six medicine classes. Our study revealed varied patterns of cardiovascular medicine use in RACFs, with 2-3 distinctive medicine use trajectories across different classes, each exhibiting a unique clinical profile, and up to a quarter of residents discontinuing a medicine class. Future studies should explore the underlying reasons and appropriateness of nonpersistence to aid in identifying areas for improvement.

Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.

Development of optimal therapeutics for disease states that can be associated with increased membrane cholesterol requires better molecular understanding of lipid modulation of the drug target. Type 1 cholecystokinin receptor (CCK1R) agonist actions are affected by increased membrane cholesterol, enhancing ligand binding and reducing calcium signaling, while agonist actions of the closely related CCK2R are not. In this work, we identified a set of chimeric human CCK1R/CCK2R mutations that exchange the cholesterol sensitivity of these 2 receptors, providing powerful tools when expressed in CHO and HEK-293 model cell lines to explore mechanisms. Static, low energy, high-resolution structures of the mutant CCK1R constructs, stabilized in complex with G protein, were not substantially different, suggesting that alterations to receptor dynamics were key to altered function. We reveal that cholesterol-dependent dynamic changes in the conformation of the helical bundle of CCK receptors affects both ligand binding at the extracellular surface and G protein coupling at the cytosolic surface, as well as their interrelationships involved in stimulus-response coupling. This provides an ideal setting for potential allosteric modulators to correct the negative impact of membrane cholesterol on CCK1R.

Lipid lowering effects of incretin-based therapies, relevant for cardiovascular benefit?

This review examines the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on lipid profiles in individuals with type 2 diabetes mellitus and/or obesity, crucial for optimizing cardiovascular risk management. GLP-1RAs affect lipid levels by reducing intestinal apolipoprotein B48 production and mesenteric lymph flow, while increasing catabolism of apolipoprotein B100. It remains unknown whether these effects are direct or indirect, but the improvements in lipid levels are strongly correlated to the drug-induced weight loss. Clinical trials demonstrate improvements in lipid profiles, with different effects per agent and dose. We deem it unlikely that improved lipid levels are sufficient to explain the beneficial effects of GLP-1RA on cardiovascular risk, especially given the improvement of many other risk factors (body weight, glycemic control, inflammation) while using these agents. Posthoc mediation analyses of large cardiovascular outcome trials may shed some light on the relative importance of each risk factor. GLP-1RAs improve lipid profiles in clinical trials, but their complete cardiovascular benefits likely involve multifactorial mechanisms beyond lipid modulation.

Lipidomics in Plants Under Abiotic Stress Conditions: An Overview

Lipids are ubiquitous macromolecules that play essential roles in several metabolic processes in plants, such as primary and secondary metabolism, energy storage, and lipid signaling, also being major constituents of membranes. Considering their importance, lipid contents, proportion, and composition are widely modulated in response to environmental conditions, which is even more important under unfavorable conditions such as abiotic stresses. In recent years, technological advances have allowed for the analysis of the global lipid profile, also known as lipidomics, which has emerged as a powerful tool for the comprehensive analysis of the modulation and roles of lipids under different conditions. This review provides a current overview of plant lipidomics research, covering the different lipid classes found in plants, analytical techniques, and the main lipid-related responses under temperature, water, salt, alkali, heavy metal, nutrient deficiency, light, and oxidative stress.

Profiling lipid changes in Panax notoginseng upon Alternaria panax infection

The growth of Panax notoginseng is stressed by various biotic and abiotic factors. Alternaria panax Whetzel is a destructive pathogen causing black spot disease of P. notoginseng, thereby severely reducing the yield and quality of P. notoginseng. However, it is still unknown in lipids change of P. notoginseng after A. panax infection. In this study, we compared the lipidomics data of normal and infected P. notoginseng to evaluate the effects of A. panax stress on lipids, and a total of 1202 lipid molecules were identified. All lipid molecules involved 34 subclasses, among which 12 subclasses were significantly up-regulated after pathogen stress. WGCNA co-expression network analysis revealed four significantly related lipid modules, including 459 lipid molecules. Differential expression analysis of all lipid molecules showed that 196 lipid molecules were significantly up-regulated and 78 lipid molecules were significantly down-regulated. The up-regulated lipid molecules were mainly Cer subclasses, while the down-regulated lipid subclasses were mainly DG, MG, PA, SQDG and SQMG. Autocorrelation analysis of differentially expressed lipid molecules showed that lipid networks in response to pathogen stress were mainly composed of lipid molecules in TG, Cer, SQDG and DGDG. Meanwhile, the lipid synthesis pathway found that 17 lipid subclasses had mutual regulatory relationships, 10 subclasses were significantly up-regulated after pathogen stress. All the results showed that these significantly different lipid molecules were involved in pathogen stress response. This study provides new reference for the search of antifungal candidate biomarkers and defense response metabolites based on lipids.

Exploring the Therapeutic Potential of Omega-3 Fatty Acid Supplementation in Dry Eye Syndrome: An In vitro Investigation

ABSTRACT Background: Dry eye syndrome (DES) is a prevalent ocular condition characterized by insufficient tear production or excessive tear evaporation, leading to discomfort and visual disturbances. Omega-3 fatty acids have been proposed as a potential therapeutic intervention for DES due to their anti-inflammatory and lipid modulation properties. Materials and Methods: Cultured human corneal epithelial cells were exposed to various concentrations of omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for 72 h. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while inflammatory cytokine levels (interleukin-6 (IL-6), interleukin-8 (IL-8)) and lipid profile (measured by lipid staining) were evaluated using enzyme-linked immunosorbent assay. Untreated cells served as controls for comparison. Results: Omega-3 fatty acid supplementation demonstrated a dose-dependent increase in cell viability compared to untreated cells. At optimal concentrations, EPA and DHA significantly enhanced cell viability by 30% and 35%, respectively (P < 0.05). Moreover, omega-3 fatty acid supplementation led to a significant reduction in inflammatory cytokine levels, with a 50% decrease in IL-6 and IL-8 secretion compared to untreated cells (P < 0.01). Additionally, lipid staining revealed improved lipid profile and organization in corneal epithelial cells following omega-3 fatty acid supplementation, indicative of enhanced tear film stability. Conclusion: In vitro findings suggest that omega-3 fatty acid supplementation exerts beneficial effects on cellular markers associated with DES.

Structure of the human K2P13.1(THIK-1) channel reveals a novel hydrophilic pore restriction and lipid cofactor site.

The halothane-inhibited K2P leak potassium channel K2P13.1 (THIK-1)1-3 is found in diverse cells1,4 including neurons1,5 and microglia6-8 where it affects surveillance6, synaptic pruning7, phagocytosis7, and inflammasome-mediated interleukin-1β release6,8,9. As with many K2Ps1,5,10-14 and other voltage-gated ion channel (VGIC) superfamily members3,15,16, polyunsaturated fatty acid (PUFA) lipids modulate K2P13.1 (THIK-1)1,5,14,17 via a poorly understood mechanism. Here, we present cryo-electronmicroscopy (cryo-EM) structures of human K2P13.1 (THIK-1) and mutants in lipid nanodiscs and detergent. These reveal that, unlike other K2Ps13,18-24, K2P13.1 (THIK-1) has a two-chamber aqueous inner cavity obstructed by a M4 transmembrane helix tyrosine (Tyr273, the flow restrictor). This hydrophilic barrier can be opened by an activatory mutation, S136P25, at natural break in the M2 transmembrane helix and by intrinsic channel dynamics. The structures also reveal a buried lipid in the P1/M4 intersubunit interface at a location, the PUFA site, that coincides with the TREK subfamily K2P modulator pocket for small molecule agonists18,26,27. This overlap, together with the effects of mutation on K2P13.1 (THIK-1) PUFA responses, indicates that the PUFA site lipids are K2P13.1 (THIK-1) cofactors. Comparison with the PUFA-responsive VGIC Kv7.1 (KCNQ1)28-31 reveals a shared role for the equivalent pore domain intersubunit interface in lipid modulation, providing a framework for dissecting the effects of PUFAs on the VGIC superfamily. Our findings reveal the unique architecture underlying K2P13.1 (THIK-1) function, highlight the importance of the P1/M4 interface in control of K2Ps by both natural and synthetic agents, and should aid development of THIK subfamily modulators for diseases such as neuroinflammation6,32 and autism6.

Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors.

Zinc is a ubiquitous contaminant in many buffers, purified products and common labware that has previously been suggested to impact on the results of functional GlyR studies and may inadvertently cause the effectiveness of some GlyR modulators to be over-estimated. This could greatly impact the assessment of potential drug-candidates and contribute to the reduced effectiveness of compounds that reach clinical stages. This is especially true for GlyR modulators being developed for pain therapeutics due to the changes in spinal zinc concentrations that have been observed during chronic pain conditions. In this study we use two-electrode voltage clamp electrophysiology to evaluate the metal chelators tricine and Ca-EDTA, and show that tricine produces inhibitory effects at GlyRα1 that are not mediated by zinc. We also utilized the zinc insensitive W170S mutation as a tool to validate metal chelators and confirm that zinc contamination has not impacted the examination of lipid modulators previously developed by our lab. This study helps to further develop methods to negate the impact of contaminating zinc in functional studies of GlyRs which should be incorporated into future studies that seek to characterize the activity of novel modulators at GlyRs.

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Identification of two archaeal GDGT lipid–modifying proteins reveals diverse microbes capable of GMGT biosynthesis and modification

Archaea produce unique membrane-spanning lipids (MSLs), termed glycerol dialkyl glycerol tetraethers (GDGTs), which aid in adaptive responses to various environmental challenges. GDGTs can be modified through cyclization, cross-linking, methylation, hydroxylation, and desaturation, resulting in structurally distinct GDGT lipids. Here, we report the identification of radical SAM proteins responsible for two of these modifications-a glycerol monoalkyl glycerol tetraether (GMGT) synthase (Gms), responsible for covalently cross-linking the two hydrocarbon tails of a GDGT to produce GMGTs, and a GMGT methylase (Gmm), capable of methylating the core hydrocarbon tail. Heterologous expression of Gms proteins from various archaea in Thermococcus kodakarensis results in the production of GMGTs in two isomeric forms. Further, coexpression of Gms and Gmm produces mono- and dimethylated GMGTs and minor amounts of trimethylated GMGTs with only trace GDGT methylation. Phylogenetic analyses reveal the presence of Gms homologs in diverse archaeal genomes spanning all four archaeal superphyla and in multiple bacterial phyla with the genetic potential to synthesize fatty acid-based MSLs, demonstrating that GMGT production may be more widespread than previously appreciated. We demonstrate GMGT production in three Gms-encoding archaea, identifying an increase in GMGTs in response to elevated temperature in two Archaeoglobus species and the production of GMGTs with up to six rings in Vulcanisaeta distributa. The occurrence of such highly cyclized GMGTs has been limited to environmental samples and their detection in culture demonstrates the utility of combining genetic, bioinformatic, and lipid analyses to identify producers of distinct archaeal membrane lipids.

Lipidomic signatures in patients with early-onset and late-onset Preeclampsia

BackgroundPreeclampsia is a pregnancy-specific clinical syndrome and can be subdivided into early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) according to the gestational age of delivery. Patients with preeclampsia have aberrant lipid metabolism. This study aims to compare serum lipid profiles of normal pregnant women with EOPE or LOPE and screening potential biomarkers to diagnose EOPE or LOPE.MethodsTwenty normal pregnant controls (NC), 19 EOPE, and 19 LOPE were recruited in this study. Untargeted lipidomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to compare their serum lipid profiles.ResultsThe lipid metabolism profiles significantly differ among the NC, EOPE, and LOPE. Compared to the NC, there were 256 and 275 distinct lipids in the EOPE and LOPE, respectively. Furthermore, there were 42 different lipids between the LOPE and EOPE, of which eight were significantly associated with fetal birth weight and maternal urine protein. The five lipids that both differed in the EOPE and LOPE were DGTS (16:3/16:3), LPC (20:3), LPC (22:6), LPE (22:6), PC (18:5e/4:0), and a combination of them were a potential biomarker for predicting EOPE or LOPE. The receiver operating characteristic analysis revealed that the diagnostic power of the combination for distinguishing the EOPE from the NC and for distinguishing the LOPE from the NC can reach 1.000 and 0.992, respectively. The association between the lipid modules and clinical characteristics of EOPE and LOPE was investigated by the weighted gene co-expression network analysis (WGCNA). The results demonstrated that the main different metabolism pathway between the EOPE and LOPE was enriched in glycerophospholipid metabolism.ConclusionsLipid metabolism disorders may be a potential mechanism of the pathogenesis of preeclampsia. Lipid metabolites have the potential to serve as biomarkers in patients with EOPE or LOPE. Furthermore, lipid metabolites correlate with clinical severity indicators for patients with EOPE and LOPE, including fetal birth weight and maternal urine protein levels.

NRF2-mediated regulation of lipid pathways in viral infection

The first line of defense against viral infection of the host cell is the cellular lipid membrane, which is also a crucial first site of contact for viruses. Lipids may sometimes be used as viral receptors by viruses. For effective infection, viruses significantly depend on lipid rafts during the majority of the viral life cycle. It has been discovered that different viruses employ different lipid raft modification methods for attachment, internalization, membrane fusion, genome replication, assembly, and release. To preserve cellular homeostasis, cells have potent antioxidant, detoxifying, and cytoprotective capabilities. Nuclear factor erythroid 2-related factor 2 (NRF2), widely expressed in many tissues and cell types, is one crucial component controlling electrophilic and oxidative stress (OS). NRF2 has recently been given novel tasks, including controlling inflammation and antiviral interferon (IFN) responses. The activation of NRF2 has two effects: it may both promote and prevent the development of viral diseases. NRF2 may also alter the host's metabolism and innate immunity during viral infection. However, its primary function in viral infections is to regulate reactive oxygen species (ROS). In several research, the impact of NRF2 on lipid metabolism has been examined. NRF2 is also involved in the control of lipids during viral infection. We evaluated NRF2's function in controlling viral and lipid infections in this research. We also looked at how lipids function in viral infections. Finally, we investigated the role of NRF2 in lipid modulation during viral infections.