Lipid Metabolome Research Articles

Berberine Mediates Exosomes Regulating the Lipid Metabolism Pathways to Promote Apoptosis of RA-FLS Cells.

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage and commonly linked to symptoms such as inflammation, swelling, and pain. Traditional Chinese Medicine offers complementary and integrative approaches in the management of rheumatoid arthritis, potentially providing additional options that may help address treatment challenges and enhance overall patient care. This paper explores the mechanism of action of berberine from the perspective of cellular exosomes by mediating exosomal contents and thus treating RA. Methods: With the help of flow cytometry and confocal laser scanning microscope, it was determined that berberine promotes apoptosis in RA-FLS cells, and then lipid metabolomics technology was applied to screen and characterize the exosomes of RA-FLS cells to identify lipid core biomarkers closely related to RA, which were then projected into various databases for comprehensive analysis. Results: The data analysis showed that berberine could call back 11 lipid core biomarkers closely associated with RA, and interactive visualization of the database revealed that these markers were mainly focused on lipid metabolism aspects such as fatty acid elongation, degradation, and biosynthesis, as well as the biosynthesis of unsaturated fatty acids or PPARA activation of gene expression, PPARα's role in lipid metabolism regulation, glycerophospholipid metabolism, mitochondrial fatty acid oxidation disorders, and organelle biogenesis and maintenance. Conclusions: Berberine exerts its therapeutic effect on RA by mediating exosomal contents and thus regulating multiple lipid-related biological pathways, affecting the PPARγ-NF-κB complex binding rate, CREB and EGR-1 expression, cellular phagocytosis, and other aspects needed to inhibit proliferation and inflammatory responses in RA-FLS. This study offers a research foundation for exploring the mechanism of action of berberine in the treatment of RA.

FABP5+ macrophages contribute to lipid metabolism dysregulation in type A aortic dissection

Type A aortic dissection (TAAD) is an acute onset disease with a high mortality rate. TAAD is caused by a tear in the aortic intima and subsequent blood infiltration. The most prominent characteristics of TAAD are aortic media degeneration and inflammatory cell infiltration, which disturb the structural integrity and function of nonimmune and immune cells in the aortic wall. However, to date, there is no systematic evaluation of the interactions between nonimmune cells and immune cells and their effects on metabolism in the context of aortic dissection. Here, multiomics, including bulk RNA-seq, single-cell RNA-seq, and lipid metabolomics, was applied to elucidate the comprehensive TAAD lipid metabolism landscape. Normally, monocytes in the stress response state secrete a variety of cytokines. Injured fibroblasts lack the ability to degrade lipids, which is suspected to contribute to a high lipid environment. Macrophages differentiate into fatty acid binding protein 5-positive (FABP5+) macrophages under the stimulation of metabolic substrates. Moreover, the upregulation of Fabp5+ macrophages were retrospectively validated in TAAD model mice and TAAD patients. Finally, Fabp5+ macrophages can generate a wide range of proinflammatory cytokines, which possibly contribute to TAAD pathogenesis.

Oxysterols contribute to immune cell recruitment in SLE skin lesions

BackgroundAbnormal oxysterol metabolism has been observed in the peripheral blood of SLE patients, but its role in systemic lupus erythematosus (SLE) skin lesions remains unclear.MethodsTargeted oxidized lipid metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS) was performed to quantify oxysterols in SLE skin lesions. Immunohistochemical staining and single-cell sequencing data analysis confirmed the upregulation of oxysterol-encoding enzymes CH25H and CYP7B1. The impact on fibroblast-mediated PBMCs chemotaxis was assessed using a transwell chamber.ResultsWe identified aberrant oxidized cholesterol metabolism in SLE skin lesions, characterized by elevated levels of 7-ketocholesterol, 5α-6α-cholestane-3β,5α,6β-triol, and so on. Fibroblasts were the primary cells expressing oxysterol-encoding genes, with CH25H and CYP7B1 expression upregulated via the IL-1β-mediated p38 MAPK and NFκB pathways. Notably, IL-1β-stimulated fibroblasts demonstrated enhanced PBMCs recruitment, which was attenuated by a GPR183 inhibitor.ConclusionOur findings reveal a potential mechanism by which fibroblasts contribute to immune cell recruitment in SLE skin lesions by expression of CH25H and CYP7B1. This study underscores the significance of oxysterol metabolism in SLE skin lesion pathogenesis and highlights potential therapeutic targets for SLE skin lesion treatment.Graphical abstract

Exploration of plasma biomarkers for Alzheimer's disease by targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy.

Alzheimer's disease (AD) is the most common cause of dementia, but the disease lacks convenient and cost-effective alternative biomarkers currently. We utilized targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy to identify plasma biomarkers in AD patients. Our study was a cross-sectional study that enrolled 58 AD patients and 40 matched health controls (HCs). Firstly, we identified plasma lipid metabolites that were significantly different between the two groups based on P < 0.05 and variable importance in the projection (VIP) > 1. Then we examined the correlation between the lipid metabolites and cognitive function using partial correlation analysis and assessed the diagnostic ability of the lipid metabolites using receiver operating characteristic (ROC) curves. Seventeen lipoproteins showed significant differences between AD patients and HCs among 114 lipid metabolites. All 17 lipoproteins were subtypes of low-density lipoprotein (LDL). Among them, LDL-3 particle number, LDL-3 apolipoprotein-B, LDL-3 phospholipids, LDL free cholesterol and LDL phospholipids were significantly correlated with cognitive function. The ROC curves showed that LDL-2 triglycerides (TG) and LDL-3 TG could significantly distinguish AD patients from HCs, with the area under the curve (AUC) above 0.7. In addition, we explored a strategy of combined diagnosis that significantly improved the diagnostic efficacy for AD (AUC = 0.879). Our study provides insight into the lipoprotein alterations associated with AD and potential biomarkers for its diagnosis and cognitive function assessment.

Morroniside repairs atrazine-induced skin damage by ameliorating lipid metabolism disorders and inhibiting ferroptosis

Morroniside (MOR) has shown great potential in treating atrazine (ATZ)-induced skin damage. This study aims to elucidate MOR's mechanism of action in mitigating lipid metabolism disorders and inhibiting ferroptosis to repair ATZ-induced skin damage. Twenty C57BL/6 mice were divided into four groups: the control group, the ATZ group, the MOR-H group and the MOR-L group, each comprising five mice. Following a one-month intervention, mouse skin tissues were harvested for untargeted lipid metabolomics analysis. Subsequently, the samples were assessed for indices related to ferroptosis. Untargeted lipid metabolomics analysis showed 127 differential metabolites in the ATZ vs. Ctrl group. There were 57 differential metabolites in the MOR-L vs. ATZ group. 34 differential metabolites in the MOR-H vs. ATZ group. the most obvious lipid reversal occurred after MOR-L administration, which primarily involved phospholipids, ceramides, and sphingomyelins. The levels of GPX4, Ferritin, MDA, SOD and GSH-PX, ferroptosis-related indicators, and the levels of p21 and p53, apoptosis-related indicators, were most significantly regressed in the MOR-L group (all P < 0.05). MOR may delay cellular aging and correct skin damage by reversing ATZ-induced lipid metabolism disorders, inhibiting ferroptosis and excessive oxidative stress occurrence.

The effects of alfalfa powder combined with health education on patients with dyslipidemia: A randomized controlled trial

BackgroundCardiovascular diseases (CVDs) remain the leading cause of global mortality, with dyslipidemia recognized as a significant risk factor. Dyslipidemia, characterized by elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), is associated with an increased lifetime risk of CVD. Although alfalfa’s cholesterol-lowering effects have been demonstrated in animal models, clinical trial data supporting its efficacy in human dyslipidemia treatment are limited. MethodsA randomized controlled trial was conducted from September 20, 2021, to January 12, 2023, involving patients diagnosed with dyslipidemia. Approved by the China Ethics Committee of Registering Clinical Trials, the study included multiple sites in China. Eligible participants were adults aged 18 years or older, meeting criteria from the Chinese Guidelines for the Prevention and Treatment of Adult Blood Lipid Disorders. Participants were randomly assigned to either a health education-only group or a combined alfalfa powder supplementation and health education group for a three-month intervention period. ResultsA total of 160 eligible patients were enrolled and randomized into two groups: the Alfalfa group (n = 80) and the Education group (n = 80). The intervention resulted in significant improvements in key lipid parameters in the Alfalfa group, including reductions in TC, LDL-C, and Apo A1 levels. Although changes in HDL-C levels were not significantly different between the groups, the Alfalfa group exhibited a larger increase. Serum lipid metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that the combined intervention did not significantly alter the overall blood lipid metabolome but identified fifteen regulated differential metabolites, with the glycerophospholipid metabolism pathway significantly affecting lipid metabolism levels. ConclusionSupplementation with alfalfa powder combined with health education significantly reduced TC, LDL-C, and Apo A1 levels in patients with dyslipidemia. KEGG pathway analysis suggests an association between the glycerophospholipid metabolism pathway and dyslipidemia. Further research is warranted to validate these findings and explore the underlying mechanisms.

Lipid Metabolomics Reveals Metabolic Responses of Subcutaneous Fat in Yaks under Different Feeding Conditions during the Cold Season

Background: The aim of this experiment was to investigate the differences in subcutaneous fat metabolism expression in yaks under natural grazing and housed feeding conditions in the cold season. Eighteen 18-month-old yaks with similar body weights and non-significant differences in dorsal subcutaneous fat were randomly divided into three groups. Methods: One group (G18_SF) of yaks was selected for slaughter at the beginning of the experiment (October), one group continued to graze for 6 months and then slaughtered (G24_SF) and one group was housed for 6 months and then slaughtered (F24_SF) and subcutaneous dorsal fat of the three groups was collected for metabolomic analysis, screening of differential metabolites and enrichment of KEGG pathway. Result: In this experiment, 110 differential metabolites were detected in G24_SF vs F24_SF and 83 metabolites were screened for down-regulation and 27 metabolites were up-regulated and the differential metabolites were mainly enriched in Alanine, aspartate and glutamate metabolism, Arachidonic acid metabolism and D-Glutamine and D-glutamate metabolism pathways. Ninety-seven differential metabolites were detected in G18_SF vs G24_SF and 41 metabolites were screened for down-regulation and 56 metabolites were screened for up-regulation, with the two groups of differential metabolites mainly enriched in Alanine, aspartate and glutamate metabolism, Caffeine metabolism and Starch and sucrose metabolism pathways. The results of this experiment revealed the information of differential metabolites and enrichment pathways of yak fat in different feeding methods and different months of age and laid the foundation for further in-depth study of subcutaneous fat deposition in yaks.

Biomarkers for congenital ventricular outflow tract malformations based on maternal serum lipid metabolomics analysis

BackgroundThe congenital ventricular outflow tract malformations (CVOTMs) is a major congenital heart diseases (CHDs) subtype, and its pathogenesis is complex and unclear. Lipid metabolic plays a crucial role in embryonic cardiovascular development. However, due to the limited types of detectable metabolites in previous studies, findings on lipid metabolic and CHDs are still inconsistent, and the possible mechanism of CHDs remains unclear.MethodsThe nest case-control study obtained subjects from the multicenter China Teratology Birth Cohort (CTBC), and maternal serum from the pregnant women enrolled during the first trimester was utilized. The subjects were divided into a discovery set and a validation set. The metabolomics of CVOTMs and normal fetuses were analyzed by targeted lipid metabolomics. Differential comparison, random forest and lasso regression were used to screen metabolic biomarkers.ResultsThe lipid metabolites were distributed differentially between the cases and controls. Setting the selection criteria of P value < 0.05, and fold change (FC) > 1.2 or < 0.833, we screened 70 differential metabolites. Within the prediction model by random forest and lasso regression, DG (14:0_18:0), DG (20:0_18:0), Cer (d18:2/20:0), Cer (d18:1/20:0) and LPC (0:0/18:1) showed good prediction effects in discovery and validation sets. Differential metabolites were mainly concentrated in glycerolipid and glycerophospholipids metabolism, insulin resistance and lipid & atherosclerosis pathways, which may be related to the occurrence and development of CVOTMs.ConclusionFindings in this study provide a new metabolite data source for the research on CHDs. The differential metabolites and involved metabolic pathways may suggest new ideas for further mechanistic exploration of CHDs, and the selected biomarkers may provide some new clues for detection of COVTMs.

Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming

BackgroundThe failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients.MethodsClinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc.ResultsTo study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis.ConclusionsWe have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.

Combined Metabolomics and Network Pharmacology Analysis Reveal the Effect of Rootstocks on Anthocyanins, Lipids, and Potential Pharmacological Ingredients of Tarroco Blood Orange (Citrus sinensis L. Osbeck).

The benefits of citrus fruits are strongly associated with their secondary metabolites. In this study, we conducted widely targeted metabolomics analyses to compare the variability of the ingredients in four scion-rootstock combinations. A total of 376 differential metabolites were obtained by a multivariate statistical analysis, and a KEGG pathway analysis showed that the enriched metabolic pathways were mainly related to the biosynthesis of flavonoids as well as lipid metabolism. The anthocyanin-targeted metabolomic features showed that cyanidin 3-O-glucoside, cyanidin 3-O-(6-O-malonyl-beta-D-glucoside), cyanidin 3-O-sophoroside, and cyanidin 3-O-xyloside were the pigments responsible for the red color of Tarocco. A lipid metabolomics analysis revealed that when Tarocco was hetero-grafted with rootstock H, there was an increase in the content of each lipid subclass, accompanied by an increase in the levels of unsaturated fatty acids, including polyunsaturated linoleic and linolenic acids, thus impacting the ratio of unsaturated fatty acids to saturated fatty acids. Additionally, we determined their antioxidant capacity ('Trifoliate orange' (Z) > 'Citrange' (ZC) > 'Hongju' (H) > 'Ziyang Xiangcheng' (X)) using in vitro assays. Finally, we utilized a network pharmacology analysis to explore the antioxidant mechanisms and potential pharmacological ingredients; we obtained 26 core targets proteins and 42 core metabolites associated with oxidative damage, providing a basis for future preventive and therapeutic applications of these metabolites.

Comparison of lipidome profiles in serum from lactating dairy cows supplemented with Acremonium terrestris culture based on UPLC-QTRAP-MS/MS

This study evaluated the effects of supplementing the diet of lactating cows with Acremonium terrestris culture (ATC) on milk production, serum antioxidant capacity, inflammatory indices, and serum lipid metabolomics. Over 90 days, 24 multiparous Chinese Holstein cows in mid-lactation (108 ± 10.4 days in milk, 637 ± 25 kg body weight, 30.23 ± 3.7 kg/d milk yield) were divided into either a control diet (CON) or a diet supplemented with 30 g of ATC daily. All the data were analyzed using Student’s t test with SPSS 20.0 software. The results showed that compared with CON feeding, ATC feeding significantly increased milk yield, antioxidant capacity, and immune function. Lipidome screening identified 143 lipid metabolites that differed between the two groups. Further analysis using “random forest” machine learning revealed three glycerophospholipid serum metabolites that could serve as lipid markers with a predictive accuracy of 91.67%. This study suggests that ATC can be a useful dietary supplement for improving lactational performance in dairy cows and provides valuable insights into developing nutritional strategies to maintain metabolic homeostasis in ruminants.

Investigating the lipid profile of Anopheles stephensi mosquitoes across developmental life stages

Holometabolous insects undergo a distinct transition in their development, tightly correlated with shifting feeding patterns from larval stages and some adult phases to non-feeding phases as pupae and during other adult phases. Furthermore, the intricate life cycle of mosquitoes involves a sequence of developmental stages influenced by aquatic and terrestrial factors, demanding precise energy resource orchestration. Lipids serve multifaceted roles, encompassing energy storage, membrane structure, and participation in signal transduction and molecular recognition processes. A significant gap in the current research landscape is the need for a comprehensive study exploring the lipid repertoire throughout the developmental stages of Anopheles stephensi mosquitoes. We undertook an analysis of the An. stephensi metabolome across all life stages. We hypothesized that An. stephensi mosquitoes will have unique lipid metabolite markers for each life stage. A specific extraction and LC-MS based lipidomic approach was used to test this hypothesis. Our findings demonstrated that our methods were successful, with lipids comprising 62.15 % of the analyzed metabolome. Additionally, phospholipids (PL), lysophospholipids (LPL), sphingomyelin (SM), and triglycerides (TG) were abundant and dynamic across all life stages. Interestingly, comparison between the L1 and L2 lipidome revealed a dominant pattern of specific TGs in decreased abundance between these two life stages. Lastly, 20-hydroxyecdysone (20E), was found to be present in similar abundance across all 4 larval stages. These data indicate that there may be lipid metabolome pathways serving unique roles during mosquito development that may be used to explore laboratory management of colonies, parasite resistance, and environmental adaptation.

The Gut Microbial Lipid Metabolite 14(15)-EpETE Inhibits Substance P Release by Targeting GCG/PKA Signaling to Relieve Cisplatin-Induced Nausea and Vomiting in Rats.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect related to activation of substance P (SP). SP activation can result from dysregulation of the gut-brain axis, and also from activation of protein kinase A signaling (PKA) signaling. In this study, we connected these factors in an attempt to unveil the mechanisms underlying CINV and develop new therapeutic strategies. Female rats were injected with cisplatin (Cis) to induce pica. Fecal samples were collected before/after injection, and subjected to lipid metabolomics analysis. In another portion of pica rats, the PKA inhibitor KT5720 was applied to investigate the involvement of PKA signaling in CINV, while fecal microbiota transplantation (FMT) was implemented to verify the therapeutic effect of the lipid metabolite 14(15)-EpETE. Pica symptoms were recorded, followed by ileal histological examination. The targeting relationship between 14(15)-EpETE and glucagon was determined by bioinformatics. SP and glucagon/PKA signaling in rat ileum, serum, and/or brain substantia nigra were detected by immunohistochemistry, enzyme-linked immunosorbent assay, and/or western blot. The results showed a significantly lower level of 14(15)-EpETE in rat feces after Cis injection. KT5720 treatment alleviated Cis-induced pica symptoms, ileal injury, SP content increase in the ileum, serum, and brain substantia nigra, and ileal PKA activation in rats. The ileal level of glucagon was elevated by Cis in rats. FMT exerted an effect similar to that of KT5720 treatment, relieving the Cis-induced changes, including ileal glucagon/PKA activation in rats. Our findings demonstrate that FMT restores 14(15)-EpETE production, which inhibits SP release by targeting GCG/PKA signaling, ultimately mitigating CINV.

Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake.

Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.

PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3β signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

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.

The mechanism of SSO regulating SiO(2)-induced lipid metabolism disorders in macrophages was explored based on lipid metabolomics

Objective: To investigate the mechanism of Sulfo-N-succinimidyloleate (SSO) regulating lipid metabolism disorder induced by silicon dioxide (SiO(2)) . Methods: In March 2023, Rat alveolar macrophages NR8383 were cultured in vitro and randomly divided into control group (C), SSO exposure group (SSO), SiO(2) exposure group (SiO(2)) and SiO(2)+SSO exposure group (SiO(2)+SSO). NR8383 cells were exposure separately or jointly by SSO and SiO(2) for 36 h to construct cell models. Immunofluorescence and BODIPY 493/ 503 staining were used to detect cluster of differentiation (CD36) and intracellular lipid levels, the protein expression levels of CD36, liver X receptors (LXR), P-mammalian target of rapamycin (P-mTOR) and cholinephosphotransferase 1 (CHPT1) were detected by Western blot, respectively, and lipid metabolomics was used to screen for different lipid metabolites and enrichment pathways. Single-factor ANOVA was used for multi-group comparison, and LSD test was used for pair-to-group comparison. Results: SiO(2) caused the expression of CD36 and P-mTOR to increase (P=0.012, 0.020), the expression of LXR to decrease (P=0.005), and the intracellular lipid level to increase. After SSO treatment, CD36 expression decreased (P=0.023) and LXR expression increased (P=0.000) in SiO(2)+SSO exposure group compared with SiO(2) exposure group. Metabolomics identified 87 different metabolites in the C group and SiO(2) exposure group, 19 different metabolites in the SiO(2) exposure group and SiO(2)+SSO group, and 5 overlaps of different metabolites in the two comparison groups, they are PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), and Sphinganine. In addition, the differential metabolites of the two comparison groups were mainly concentrated in the glycerophospholipid metabolism and sphingolipid metabolism pathways. The differential gene CHPT1 in glycerophospholipid metabolic pathway was verified, and the expression of CHPT1 decreased after SiO(2) exposure. Conclusion: SSO may improve SiO(2)-induced lipid metabolism disorders by regulating PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), SPA, glycerophospholipid metabolism and sphingolipid metabolism pathways.

Spatial multi-omics characterizes GPR35-relevant lipid metabolism signatures across liver zonation in MASLD

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and cancer. The zonal distribution of biomolecules in the liver is implicated in mediating the disease progression. Recently, G-protein-coupled receptor 35 (GPR35) has been highlighted to play a role in MASLD, but the precise mechanism is not fully understood, particularly, in a liver-zonal manner. Here, we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD, by combining lipid metabolomics, spatial transcriptomics (ST), and spatial metabolomics (SM). We found that GPR35 influenced lipid accumulation, inflammatory and metabolism-related factors in specific regions, notably affecting the anti-inflammation factor ELF4 (E74 like E-twenty six (ETS) transcription factor 4), lipid homeostasis key factor CIDEA (cell death-inducing DNA fragmentation factor alpha (DFFA)-like effector A), and the injury response-related genes SAA1/2/3 (serum amyloid A1/2/3), thereby impacting MASLD progression. Furthermore, SM elucidated specific metabolite distributions across different liver regions, such as C10H11N4O7P (3ʹ,5ʹ-cyclic inosine monophosphate (3ʹ,5ʹ-IMP)) for the central vein, and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression. Taken together, GPR35 regulates hepatocyte damage repair, controls inflammation, and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.

Codonopsis pilosula-derived glycopeptide dCP1 promotes the polarization of tumor-associated macrophage from M2-like to M1 phenotype

The majority of the immune cell population in the tumor microenvironment (TME) consists of tumor-associated macrophages (TAM), which are the main players in coordinating tumor-associated inflammation. TAM has a high plasticity and is divided into two main phenotypes, pro-inflammatory M1 type and anti-inflammatory M2 type, with tumor-suppressive and tumor-promoting functions, respectively. Considering the beneficial effects of M1 macrophages for anti-tumor and the high plasticity of macrophages, the conversion of M2 TAM to M1 TAM is feasible and positive for tumor treatment. This study sought to evaluate whether the glycopeptide derived from simulated digested Codonopsis pilosula extracts could regulate the polarization of M2-like TAM toward the M1 phenotype and the potential regulatory mechanisms. The results showed that after glycopeptide dCP1 treatment, the mRNA relative expression levels of some M2 phenotype marker genes in M2-like TAM in simulated TME were reduced, and the relative expression levels of M1 phenotype marker genes and inflammatory factor genes were increased. Analysis of RNA-Seq of M2-like TAM after glycopeptide dCP1 intervention showed that the gene sets such as glycolysis, which is associated with macrophage polarization in the M1 phenotype, were significantly up-regulated, whereas those of gene sets such as IL-6-JAK-STAT3 pathway, which is associated with polarization in the M2 phenotype, were significantly down-regulated. Moreover, PCA analysis and Pearson's correlation also indicated that M2-like TAM polarized toward the M1 phenotype at the transcriptional level after treatment with the glycopeptide dCP1. Lipid metabolomics was used to further explore the efficacy of the glycopeptide dCP1 in regulating the polarization of M2-like TAM to the M1 phenotype. It was found that the lipid metabolite profiles in dCP1-treated M2-like TAM showed M1 phenotype macrophage lipid metabolism profiles compared with blank M2-like TAM. Analysis of the key differential lipid metabolites revealed that the interconversion between phosphatidylcholine (PC) and diacylglycerol (DG) metabolites may be the central reaction of the glycopeptide dCP1 in regulating the conversion of M2-like TAM to the M1 phenotype. The above results suggest that the glycopeptide dCP1 has the efficacy to regulate the polarization of M2-like TAM to M1 phenotype in simulated TME.

Lipid metabolism mediates the association between body mass index change and bone mineral density: The Taizhou imaging study

BackgroundLimited research explores the impact of body mass index (BMI) change on osteoporosis, regarding the role of lipid metabolism. We aimed to cross-sectionally investigate these relationships in 820 Chinese participants aged 55–65 from the Taizhou Imaging Study. MethodsWe used the baseline data collected between 2013 and 2018. T-score was calculated by standardizing bone mineral density and was used for osteoporosis and osteopenia diagnosis. Multinomial logistic regression was used to examine the effect of BMI change on bone health status. Multivariable linear regression was employed to identify the metabolites corrected with BMI change and T-score. Exploratory factor analysis (EFA) and mediation analysis were conducted to ascertain the involvement of the metabolites. ResultsBMI increase served as a protective factor against osteoporosis (OR = 0.79[0.71–0.88], P-value<0.001) and osteopenia (OR = 0.88[0.82–0.95], P-value<0.001). Eighteen serum metabolites were associated with both BMI change and T-score. Specifically, high-density lipoprotein (HDL) substructures demonstrated negative correlations (β = −0.08 to −0.06 and − 0.12 to −0.08, respectively), while very low-density lipoprotein (VLDL) substructions showed positive correlations (β = 0.09 to 0.10 and 0.10 to 0.11, respectively). The two lipid factors (HDL and VLDL) extracted by EFA acted as mediators between BMI change and T-score (Prop. Mediated = 8.16% and 10.51%, all P-value<0.01). ConclusionBMI gain among Chinese aged 55–65 is beneficial for reducing the risk of osteoporosis. The metabolism of HDL and VLDL partially mediates the effect of BMI change on bone loss. Our research offers novel insights into the prevention of osteoporosis, approached from the perspective of weight management and lipid metabolomics.