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Metabolism: Clinical and Experimental Jun 2024Bariatric surgery improves metabolic health, but the underlying mechanisms are not fully understood. We analyzed the effects of two types of bariatric surgery, sleeve...
OBJECTIVES
Bariatric surgery improves metabolic health, but the underlying mechanisms are not fully understood. We analyzed the effects of two types of bariatric surgery, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), on the plasma metabolome and lipidome.
METHODS
We characterized the plasma metabolome (1268 metabolites) and lipidome (953 lipids) pre-operatively and at 3 and 12 months post-operatively in 104 obese adults who were previously recruited to a prospective cohort of bariatric surgery. The metabolomic and lipidomic responses to bariatric surgery over time were analyzed using multivariable linear mixed-effects models.
RESULTS
There were significant changes in multiple metabolites and lipids, including rapid early changes in amino acid and peptide metabolites, including decreases in branched-chain amino acids (BCAAs), aromatic AAs, alanine and aspartate, and increases in glycine, serine, arginine and citrulline. There were also significant decreases in many triglyceride species, with increases in phosphatidylcholines and phosphatidylethanolamines. There were significant changes in metabolites related to energy metabolism that were apparent only after 12 months. We observed differences by bariatric surgery type in the changes in a small number of primary and secondary bile acids, including glycohyocholate and glyco-beta-muricholate.
CONCLUSIONS
Our findings highlight the comprehensive changes in metabolites and lipids that occur over the 12 months following bariatric surgery. While both SG and RYGB caused profound changes in the metabolome and lipidome, RYGB was characterized by greater increases in bile acids following surgery.
PubMed: 38906372
DOI: 10.1016/j.metabol.2024.155955 -
Journal of Molecular Modeling Jun 2024Electroporation is a technique that creates electrically generated pores in the cell membrane by modifying transmembrane potential. In this work, the finite element...
CONTEXT
Electroporation is a technique that creates electrically generated pores in the cell membrane by modifying transmembrane potential. In this work, the finite element method (FEM) was used to examine the induced transmembrane voltage (ITV) of a spherical-shaped MCF-7 cell, allowing researchers to determine the stationary ITV. A greater ITV than the critical value causes permeabilization of the membrane. Furthermore, the present study shows how a specific surface conductivity can act as a stand-in for the thin layer that constitutes a cell membrane as the barrier between extracellular and intracellular environments. Additionally, the distribution of ITV on the cell membrane and its maximum value were experimentally evaluated for a range of applied electric fields. Consequently, the entire cell surface area was electroporated 66% and 68% for molecular dynamics (MD) simulations and FEM, respectively, when the external electric field of 1500 V/cm was applied to the cell suspension using the previously indicated numerical methods. Furthermore, the lipid bilayers' molecular structure was changed, which led to the development of hydrophilic holes with a radius of 1.33 nm. Applying MD and FEM yielded threshold values for transmembrane voltage of 700 and 739 mV, respectively.
METHOD
Using MD simulations of palmitoyloleoyl-phosphatidylcholine (POPC), pores in cell membranes exposed to external electric fields were numerically investigated. The dependence on the electric field was estimated and developed, and the amount of the electroporated cell surface area matches the applied external electric field. To investigate more, a mathematical model based on an adaptive neuro-fuzzy inference system (ANFIS) is employed to predict the percent cell viability of cancerous cells after applying four pulses during electroporation. For MD simulations, ArgusLab, VMD, and GROMACS software packages were used. Moreover, for FEM analysis, COMSOL software package was used. Also, it is worth mentioning that for mathematical model, MATLAB software is used.
Topics: Molecular Dynamics Simulation; Humans; Cell Membrane; Electroporation; Finite Element Analysis; Lipid Bilayers; Membrane Potentials; MCF-7 Cells; Electricity; Cell Membrane Permeability; Phosphatidylcholines
PubMed: 38904863
DOI: 10.1007/s00894-024-06012-0 -
The Journal of Physical Chemistry. B Jun 2024Ceramide transfer protein CERT is the mediator of nonvesicular transfer of ceramide from the ER to Golgi. In CERT, START is the domain responsible for the binding and...
Ceramide transfer protein CERT is the mediator of nonvesicular transfer of ceramide from the ER to Golgi. In CERT, START is the domain responsible for the binding and transport of ceramide. A wealth of structural data has revealed a helix-grip fold surrounding a large hydrophobic cavity holding the ceramide. Yet, little is known about the mechanisms by which START releases the ceramide through the polar region and into the packed environment of cellular membranes. As such events do not lend themselves easily to experimental investigations, we used multiple unbiased microsecond-long molecular simulations. We propose a membrane-assisted mechanism in which the membrane acts as an allosteric effector initiating the release of ceramide and where the passage of the ceramide acyl chains is facilitated by the intercalation of a single phosphatidylcholine lipid in the cavity, practically greasing the ceramide way out. We verify using free energy calculation and experimental lipidomics data that CERT forms stable complexes with phosphatidylcholine lipids, in addition to ceramide, thus providing validation for the proposed mechanism.
PubMed: 38903016
DOI: 10.1021/acs.jpcb.4c02398 -
BMC Genomics Jun 2024Global per capita meat consumption continues to rise, especially pork. Meat quality is influenced by the content of intramuscular fat (IMF) as a key factor. The...
BACKGROUND
Global per capita meat consumption continues to rise, especially pork. Meat quality is influenced by the content of intramuscular fat (IMF) as a key factor. The longissimus dorsi muscle of Dahe pigs (DHM, IMF: 7.98% ± 1.96%) and Dahe black pigs (DHBM, IMF: 3.30% ± 0.64%) was studied to explore cellular heterogeneity and differentially expressed genes (DEGs) associated with IMF deposition using single-nucleus RNA sequencing (snRNA-seq). The lipid composition was then analyzed using non-targeted lipidomics.
RESULTS
A total of seven cell subpopulations were identified, including myocytes, fibroblast/fibro/adipogenic progenitors (FAPs), satellite cells, endothelial cells, macrophages, pericytes, and adipocytes. Among them, FAPs and adipocytes were more focused because they could be associated with lipid deposition. 1623 DEGs in the FAPs subpopulation of DHBM were up-regulated compared with DHM, while 1535 were down-regulated. These DEGs enriched in the glycolysis/gluconeogenesis pathway. 109 DEGs were up-regulated and 806 were down-regulated in the adipocyte subpopulation of DHBM compared with DHM, which were mainly enriched in the PPAR signaling pathway and fatty acid (FA) biosynthesis. The expression level of PPARG, ABP4, LEP, and ACSL1 genes in DHM was higher than that in DHBM. Lipidomics reveals porcine lipid composition characteristics of muscle tissue. A total of 41 lipid classes and 2699 lipid species were identified in DHM and DHBM groups. The top ten relative peak areas of lipid classes in DHM and DHBM were triglyceride (TG), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), diglyceride (DG), cardiolipin (CL), ceramides (Cer), Simple Glc series (Hex1Cer), sphingomyelin (phSM), and phosphatidylinositol (PI). The relative peak areas of 35 lipid species in DHM were lower than DHBM, and 28 lipid species that were higher. There was a significant increase in the TG fatty acyl chains C6:0, C17:0, and C11:4, and a significant decrease in C16:0, C18:1, C18:2, and C22:4 in DHBM (p < 0.05).
CONCLUSIONS
C16:0 FA may downregulate the expression level of PPARG gene, which leads to the downregulation of fat metabolism-related genes such as ACSL, PLIN2, and FABP4 in DHBM compared with DHM. This may be the reason that the lipid deposition ability of Dahe pigs is stronger than that of Dahe black pigs, which need further investigation.
Topics: Animals; Swine; Muscle, Skeletal; Lipid Metabolism; Lipidomics; Sequence Analysis, RNA; Single-Cell Analysis; Lipids; Gene Expression Profiling
PubMed: 38902599
DOI: 10.1186/s12864-024-10488-8 -
Communications Biology Jun 2024Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety...
Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.
Topics: Animals; Emulsifying Agents; Dysbiosis; Gastrointestinal Microbiome; Mice; Male; Metabolic Diseases; Mice, Inbred C57BL; Carboxymethylcellulose Sodium; Sucrose; Insulin Resistance; Lecithins
PubMed: 38902371
DOI: 10.1038/s42003-024-06224-3 -
The Journal of Nutrition Jun 2024Healthy plant-based diets have been associated with lower risk of type 2 diabetes (T2D). Metabolomics can be leveraged to identify potential pathways through which diet...
BACKGROUND
Healthy plant-based diets have been associated with lower risk of type 2 diabetes (T2D). Metabolomics can be leveraged to identify potential pathways through which diet influences disease risk.
OBJECTIVE
To identify profiles of serum metabolites reflective of plant-based diets of varying quality and examine associations with cardiometabolic risk and T2D.
METHODS
We included data from 687 participants of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort. An overall plant-based diet index (PDI), healthy PDI (hPDI), and unhealthful PDI (uPDI) were estimated from food frequency questionnaires. Serum metabolites were assayed using ultra-performance liquid chromatography mass spectrometry. Elastic net regression was used to identify sets of metabolites predictive of each diet index and metabolite profile scores were calculated as the weighted sum of the selected metabolites. Cross-sectional associations between metabolite profile scores and cardiometabolic measures and prospective associations with incident T2D were evaluated with multivariable adjusted linear and logistic regressions.
RESULTS
Metabolite profiles for PDI, hPDI, and uPDI consisted of n=51, 55, and 45 metabolites, respectively. Metabolites strongly positively correlated with diet indices included phosphatidylcholine (16:0/18:3) for PDI, phosphatidylethanolamine (20:1/20:4) and pantothenate for hPDI, and lysophosphatidylglycerol (18:2/0:0), proline, and lauric acid for uPDI. Higher metabolite profile scores for PDI and hPDI were associated with lower glycemia and lipids measures, whereas a higher uPDI metabolite score was associated with higher triglycerides and lower LDL-C and HDL-C. A higher metabolite score for hPDI was additionally associated with lower adiposity measures, higher liver fat attenuation, higher adiponectin), lower odds of overweight and obesity (OR 0.64 [95% CI: 0.51-0.81] and 0.59 [95% CI: 0.48-0.74], respectively) and lower odds of incident T2D (OR 0.66 [95% CI: 0.45-0.97]).
CONCLUSION
Metabolite profiles of different plant-based diets were identified. Metabolite profiles of overall and healthy plant-based diets were associated with favorable cardiometabolic risk profiles.
PubMed: 38901635
DOI: 10.1016/j.tjnut.2024.06.007 -
International Journal of Pharmaceutics Jun 2024Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By...
Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.
PubMed: 38901537
DOI: 10.1016/j.ijpharm.2024.124367 -
Journal of Chromatography. B,... Jun 2024Lipidomics is focusing on the screening of lipid species in complex mixtures using mass spectrometry-based approaches. In this work, we aim to enhance the intestinal...
Lipidomics is focusing on the screening of lipid species in complex mixtures using mass spectrometry-based approaches. In this work, we aim to enhance the intestinal lipidome coverage within the Oligo-Mouse-Microbiota (OMM) colonized mouse model by testing eight mobile phase conditions on five reversed-phase columns. Our selected mobile phase modifiers included two ammonium salts, two concentrations, and the addition of respective acids at 0.1 %. We compared two columns with hybrid surface technology, two with ethylene bridged hybrid technology and one with core-shell particles. Best performance was attained for standards and intestinal lipidome, using either ammonium formate or acetate in ESI(+) or ammonium acetate in ESI(-) for all column technologies. Notably, a concentration of 5 mM ammonium salt showed optimal results for both modes, while the addition of acids had a negligible effect on lipid ionization efficiency. The HST BEH C18 column improved peak width and tailing factor parameters compared to other technologies. We achieved the highest lipid count in colon and ileum content, including ceramides, phosphatidylethanolamines and phosphatidylcholines, when using 5 mM ammonium acetate in ESI(-). Conversely, in ESI(+) 5 mM ammonium formate demonstrated superior coverage for diacylglycerols and triacylglycerols.
PubMed: 38901159
DOI: 10.1016/j.jchromb.2024.124188 -
Cell Reports Jun 2024Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and...
Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68 monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68 monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68 and CD68 monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.
PubMed: 38900640
DOI: 10.1016/j.celrep.2024.114370 -
Hepatology (Baltimore, Md.) Jun 2024Liver hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of...
BACKGROUND AND AIMS
Liver hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature.
APPROACH AND RESULTS
Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine (PC), and sphingolipid (SL) derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids (SFA-PC) and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) and Ceramide Synthase 5 (CERS5) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy.
CONCLUSION
In conclusion, our study elucidates the metabolic reprogramming gnature of lipid metabolism in HCC, identifies prognostic markers, and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.
PubMed: 38899975
DOI: 10.1097/HEP.0000000000000962