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IntroductionCD5L is a scavenger receptor-like molecule that mediates diverse physiologic processes, including cell survival, atherogenesis, inflammation, and lipid metabolism. Even though CD5L is an abundant circulatory protein, it has recently become apparent that its expression can alter inflammatory signaling in a cell-autonomous fashion. To date, the effect of endogenous CD5L expression in human macrophages remains largely unexplored. Our work addressed this question by analyzing the impact of CD5L gene disruption on the inflammatory state of the THP-1 human monocytic cell line.ResultsIn macrophage-like CD5L-knockout cells, we observed a dramatic decrease in the basal expression of a subset of NF-κB-regulated genes when compared to control cell lines. These differences persisted after stimulation with lipopolysaccharide (LPS), even though the magnitude of induction was similar in both mutant and control cells. Consistent with the lipid remodeling function attributed to CD5L, we found significant changes in the makeup of the intracellular lipid pool. However, we did not detect significant changes in the activity of fatty acid synthase, which has been suggested to mediate CD5L lipidome remodeling function. Furthermore, we explored how CD5L function impacts undifferentiated monocytes. We found that in undifferentiated, unstimulated monocytes deleted for CD5L, several dysregulated transcripts code for genes involved in cell-to-cell interactions and in the progression of atherosclerosis. Most importantly, we found that CD5L deletion upregulates the expression of CD52, a novel anti-inflammatory switch.DiscussionOverall, our findings further support the multifunctional nature of CD5L and, for the first time, suggest its involvement in monocyte localization to sites of future lesions.

Abstract Background and Hypothesis Multiple lines of clinical, biochemical, and genetic evidence suggest that disturbances of membrane lipids and their metabolism are probably involved in the etiology of schizophrenia (SCZ). Lipids in the membrane are essential to neural development and brain function, however, their role in SCZ remains largely unexplored. Study Design Here we investigated the lipidome of the erythrocyte membrane of 80 patients with SCZ and 40 healthy controls using ultra-performance liquid chromatography-mass spectrometry. Based on the membrane lipids profiling, we explored the potential mechanism of membrane phospholipids metabolism. Study Results By comparing 812 quantified lipids, we found that in SCZ, membrane phosphatidylcholines and phosphatidylethanolamines, especially the plasmalogen, were significantly decreased. In addition, the total polyunsaturated fatty acids (PUFAs) in the membrane of SCZ were significantly reduced, resulting in a decrease in membrane fluidity. The accumulation of membrane oxidized lipids and the level of peripheral lipid peroxides increased, suggesting an elevated level of oxidative stress in SCZ. Further study of membrane-phospholipid-remodeling genes showed that activation of PLA2s and LPCATs expression in patients, supporting the imbalance of unsaturated and saturated fatty acyl remodeling in phospholipids of SCZ patients. Conclusions Our results suggest that the mechanism of impaired membrane lipid homeostasis is related to the activated phospholipid remodeling caused by excessive oxidative stress in SCZ. Disordered membrane lipids found in this study may reflect the membrane dysfunction in the central nervous system and impact neurotransmitter transmission in patients with SCZ, providing new evidence for the membrane lipids hypothesis of SCZ.

Strong evidence suggests that differences in the molecular composition of lipids in exosomes depend on the cell type and has an influence on cancer initiation and progression. Here, we analyzed by liquid chromatography–mass spectrometry (LC‐MS) the lipidomic signature of exosomes derived from the human cell lines normal colon mucosa (NCM460D), and colorectal cancer (CRC) nonmetastatic (HCT116) and metastatic (SW620), and exosomes isolated from the plasma of nonmetastatic and metastatic CRC patients and healthy donors. Analysis of this exhaustive lipid study highlighted changes in some molecular species that were found in the cell lines and confirmed in the patients. For example, exosomes from primary cancer patients and nonmetastatic cells compared with healthy donors and control cells displayed a common marked increase in phosphatidylcholine (PC) 34 : 1, phosphatidylethanolamine (PE) 36 : 2, sphingomyelin (SM) d18 : 1/16 : 0, hexosylceramide (HexCer) d18 : 1/24 : 0 and HexCer d18 : 1/24 : 1. Interestingly, these same lipids species were decreased in the metastatic cell line and patients. Further, levels of PE 34 : 2, PE 36 : 2, and phosphorylated PE p16 : 0/20 : 4 were also significantly decreased in metastatic conditions when compared to the nonmetastatic counterparts. The only molecule species found markedly increased in metastatic conditions (in both patients and cells) when compared to controls was ceramide (Cer) d18 : 1/24 : 1. These decreases in lipid species in the extracellular vesicles might reflect function‐associated changes in the metastatic cell membrane. Although these potential biomarkers need to be validated in a larger cohort, they provide new insight toward the use of clusters of lipid biomarkers rather than a single molecule for the diagnosis of different stages of CRC. Lipid dysregulation‐induced structural changes of the plasma membrane in cancer modulate cellular homeostasis, signaling pathways, and can affect colorectal cancer (CRC) initiation and progression. Since these changes are also found in the membrane lipid bilayer of the tumor‐released exosomes, mass spectroscopy can help to define an exosomal lipidomic signature to find noninvasive circulant diagnostic/prognostic biomarkers for different CRC stages.

Systemic immune inflammation is a key mediator in the progression of coronary artery disease (CAD), concerning various metabolic and lipid changes. In this study, the relationship between the inflammatory index and metabolic profile in patients with CAD was investigated to provide deep insights into metabolic disturbances related to inflammation. Widely targeted plasma metabolomic and lipidomic profiling was performed in 1,234 patients with CAD. Laboratory circulating inflammatory markers were mainly used to define general systemic immune and low-grade inflammatory states. Multivariable-adjusted linear regression was adopted to assess the associations between 860 metabolites and 7 inflammatory markers. Least absolute shrinkage and selection operator (LASSO) logistic-based classifiers and multivariable logistic regression were applied to identify biomarkers of inflammatory states and develop models for discriminating an advanced inflammatory state. Multiple metabolites and lipid species were linearly associated with the seven inflammatory markers [false discovery rate (FDR) <0.05]. LASSO and multivariable-adjusted logistic regression analysis identified significant associations between 45 metabolites and systemic immune-inflammation index, 46 metabolites and neutrophil-lymphocyte ratio states, 32 metabolites and low-grade inflammation score, and 26 metabolites and high-sensitivity C-reactive protein states ( < 0.05). Glycerophospholipid metabolism and arginine and proline metabolism were determined as key altered metabolic pathways for systemic immune and low-grade inflammatory states. Predictive models based solely on metabolite combinations showed feasibility (area under the curve: 0.81 to 0.88) for discriminating the four parameters that represent inflammatory states and were successfully validated using a validation cohort. The inflammation-associated metabolite, namely, β-pseudouridine, was related to carotid and coronary arteriosclerosis indicators ( < 0.05). This study provides further information on the relationship between plasma metabolite profiles and inflammatory states represented by various inflammatory markers in CAD. These metabolic markers provide potential insights into pathological changes during CAD progression and may aid in the development of therapeutic targets.

Haematococcus pluvialis cells predominantly remain in the macrozooid stage under favourable environmental conditions but are rapidly differentiated into haematocysts upon exposure to various environmental stresses. Haematocysts are characterized by massive accumulations of astaxanthin sequestered in cytosolic oil globules. Lipidomic analyses revealed that synthesis of the storage lipid triacylglycerol (TAG) was substantially stimulated under high irradiance. Simultaneously, remodelling of membrane glycerolipids occurred as a result of dramatic reductions in chloroplast membrane glycolipids but remained unchanged or declined slightly in extraplastidic membrane glycerolipids. De novo assembly of transcriptomes revealed the genomic and metabolic features of this unsequenced microalga. Comparative transcriptomic analysis showed that so-called resting cells (haematocysts) may be more active than fast-growing vegetative cells (macrozooids) regarding metabolic pathways and functions. Comparative transcriptomic analyses of astaxanthin biosynthesis suggested that the non-mevalonate pathway mediated the synthesis of isopentenyl diphosphate, as the majority of genes involved in subsequent astaxanthin biosynthesis were substantially up-regulated under high irradiance, with the genes encoding phytoene synthase, phytoene desaturase, and β-carotene hydroxylase identified as the most prominent regulatory components. Accumulation of TAG under high irradiance was attributed to moderate up-regulation of de novo fatty acid biosynthesis at the gene level as well as to moderate elevation of the TAG assembly pathways. Additionally, inferred from transcriptomic differentiation, an increase in reactive oxygen species (ROS) scavenging activity, a decrease in ROS production, and the relaxation of over-reduction of the photosynthetic electron transport chain will work together to protect against photooxidative stress in H. pluvialis under high irradiance.

Low temperature is one of the major abiotic stresses that restrict the growth and development of maize seedlings. Membrane lipid metabolism and remodeling are key strategies for plants to cope with temperature stresses. In this study, an integrated lipidomic and transcriptomic analysis was performed to explore the metabolic changes of membrane lipids in the roots of maize seedlings under cold stress (5°C). The results revealed that major extraplastidic phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), and phosphatidylinositol (PI)] were dominant membrane lipids in maize root tissues, accounting for more than 70% of the total lipids. In the transcriptome data of maize roots under cold stress, a total of 189 lipid-related differentially expressed genes (DEGs) were annotated and classified into various lipid metabolism pathways, and most of the DEGs were enriched in the “Eukaryotic phospholipid synthesis” (12%), “Fatty acid elongation” (12%), and “Phospholipid signaling” (13%) pathways. Under low temperature stress, the molar percentage of the most abundant phospholipid PC decreased around 10%. The significantly up-regulated expression of genes encoding phospholipase [phospholipase D (PLD)] and phosphatase PAP/LPP genes implied that PC turnover was triggered by cold stress mainly via the PLD pathway. Consequently, as the central product of PC turnover, the level of PA increased drastically (63.2%) compared with the control. The gene-metabolite network and co-expression network were constructed with the prominent lipid-related DEGs to illustrate the modular regulation of metabolic changes of membrane lipids. This study will help to explicate membrane lipid remodeling and the molecular regulation mechanism in field crops encountering low temperature stress.

Dynamic changes in circulating and tissue metabolites and lipids occur in response to exercise-induced cellular and whole-body energy demands to maintain metabolic homeostasis. The metabolome and lipidome in a given biological system provides a molecular snapshot of these rapid and complex metabolic perturbations. The application of metabolomics and lipidomics to map the metabolic responses to an acute bout of aerobic/endurance or resistance exercise has dramatically expanded over the past decade thanks to major analytical advancements, with most exercise-related studies to date focused on analyzing human biofluids and tissues. Experimental and analytical considerations, as well as complementary studies using animal model systems, are warranted to help overcome challenges associated with large human interindividual variability and decipher the breadth of molecular mechanisms underlying the metabolic health-promoting effects of exercise. In this review, we provide a guide for exercise researchers regarding analytical techniques and experimental workflows commonly used in metabolomics and lipidomics. Furthermore, we discuss advancements in human and mammalian exercise research utilizing metabolomic and lipidomic approaches in the last decade, as well as highlight key technical considerations and remaining knowledge gaps to continue expanding the molecular landscape of exercise biology.

Major depressive disorder (MDD) is a highly prevalent psychiatric condition with complex and heterogeneous biological underpinnings. Lipid dysregulation has emerged as a potential contributor to MDD pathophysiology. However, comprehensive lipidomic profiling studies in Japanese individuals remain limited. This study aimed to investigate serum lipidomic alterations in Japanese patients with MDD and explore the potential associations with depression severity. We conducted a real-world observational study including 30 Japanese patients with MDD and 30 healthy controls. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale. Lipidomic analysis identified 344 lipid peaks from serum samples. Multivariate and univariate statistical analyses were employed to identify differentially expressed lipids and their correlations with clinical symptoms. Thirty lipids were found to differ significantly between groups, with 7 elevated and 23 reduced in the MDD cohort. Pathway enrichment analysis highlighted disruptions in lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), N-acylethanolamines, and fatty acylcarnitines. Notably, levels of LPC (20:3), platelet-activating factor (20:5), and platelet-activating factor (18:3) were negatively correlated with depression severity, suggesting a potential link to mood regulation. The pronounced enrichment changes observed in LPC and LPE-lipid species involved in membrane remodeling and cellular signal transduction-are consistent with previous findings. However, the observed negative correlations with psychiatric symptom severity were contrary to prior expectations. These results underscore the importance of interpreting lipidomic data in the context of specific population characteristics, methodological frameworks, and clinical settings. They suggest potentially meaningful metabolic alterations associated with MDD and provide a foundation for future longitudinal and mechanistic investigations.

Objective This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method. Method The study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The study assessed heterogeneity and horizontal pleiotropy through Cochran's Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study. Results By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER + BC), phosphatidylcholine ( P  < 0.05) and phosphatidylinositol (OR: 0.916–0.966, P  < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P  < 0.001) and triacylglycerol, OR: 0.894–0.960, P  < 0.05)). However, the study did not observe a noteworthy impact of sphingolipids on ER + BC. In the case of estrogen receptor-negative BC (ER − BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P  = 0.008), and glycerolipids (OR = 0.909, P  = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034–1.056, P  < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091–1.119, P  < 0.05) was an important causal effect in ER − BC. Conclusions The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the study elucidates BC's intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.