Journal of Lipid Research最新文献

The aim of this study was to investigate whether cholesterol metabolism, especially high cholesterol absorption, affects atherosclerotic event risk in acute coronary syndrome (ACS) versus control patients without coronary artery disease (CAD). We set up a randomized, case-control substudy of a Corogene cohort (total cohort 5,295 consecutive patients admitted for coronary angiography because of stable or atypical chest pains and followed up for a median of 9.5 [interquartile range, 8.9-10.0] years). Of these, 200 ACS patients were matched by sex, age, BMI, LDL-C, and serum triglycerides to 200 patients without CAD. Blood samples were available in 363 cases (study population: ACS, n = 168; no CAD, n = 195) for analysis of serum biomarkers of relative cholesterol metabolism. High cholesterol absorption was associated with nonfatal and fatal acute CAD events in the ACS group but not in the no CAD group, whereas good compliance with statin treatment during the follow-up and low LDL-C concentration associated with good prognosis. Patients with high cholesterol absorption showed the worst survival probability during the follow-up, whereas individuals with low cholesterol absorption showed the best survival probability. In conclusion, high cholesterol absorption was associated with nonfatal and fatal acute CAD events in the ACS group in this exploratory clinical study. Individuals with high cholesterol absorption had more atherosclerotic events during the follow-up period, and their survival rate was worse than that of those with low cholesterol absorption. With therapy lowering both cholesterol absorption and LDL-C concentrations, cholesterol metabolism can be modified to become less atherogenic.

Multiple synthetic high-density lipoproteins (sHDLs) have been developed and extensively evaluated in preclinical and clinical trials, with their functionality potentially linked to specific lipid compositions. This study investigates how lipid composition influences sHDL interactions with platelets. We synthesized sHDL particles using ApoA1 mimetic peptide 22A complexed with various lipids (DMPC, POPC, DSPC, DPPC, and SM) differing in chain lengths, saturation levels, and transition temperatures. DMPC sHDL demonstrated superior inhibition of platelet aggregation across multiple agonist concentrations, while POPC sHDL showed limited efficacy only at lower thrombin concentrations. Interestingly, all formulations exhibited similar cholesterol removal abilities, and POPC sHDL demonstrated the highest platelet association despite its inferior antiplatelet effects. Mechanistic investigation revealed the involvement of phospholipase A₂ (PLA₂) enzymes in DMPC sHDL's potent antiplatelet effects. Inhibition of cytosolic PLA₂ (cPLA₂) and lipoprotein-associated PLA₂ (Lp-PLA₂) significantly reduced DMPC sHDL's antiplatelet activity. We demonstrated PLA₂-mediated hydrolysis of DMPC sHDL, resulting in bioactive lipid metabolites, lysophosphatidylcholine (LPC) 14:0 and myristic acid, both in vitro and in vivo. These metabolites directly inhibited platelet aggregation, integrin activation, and α-granule secretion in a dose-dependent manner, with significantly greater potency than metabolites derived from other phospholipids. Our findings elucidate a novel mechanism by which sHDL's lipid composition influences its antiplatelet properties through the generation of bioactive lipid metabolites, offering insights for developing targeted cardiovascular therapies.

The regular use of commercially available Standard Reference Materials (SRM) and intralaboratory quality control materials, which are important tools, is essential for standardizing and ensuring high-quality lipidomic analyses. These materials should also be relevant for the research application. To support nutritional lipidomic research, the global lipidome of materials derived from individuals consuming a range of n-3 PUFAs was determined. Nontargeted lipidomics were completed on SRM 2378 (serum), SRM 1950 (plasma), and intralaboratory quality control (plasma) generated from individuals with low omega-3 and high omega-3 status. SRM 2378 includes materials generated from individuals consuming fish oil (SRM 2378-1), flaxseed oil (SRM 2378-2), and no supplements (SRM 2378-3). Specific lipids with differences were identified using fold-based and absolute differences in semiquantitated concentrations. Individual lipids containing 20:5 and 22:6 were highly variable and largely reflected ad hoc intake estimates of EPA and DHA. Fold-based approaches identified low-abundant lipids that differed, whereas absolute differences identified high-abundant lipid species that differed. In addition, differences due to dietary fatty acid intakes were more dramatic than differences between serum and plasma in these nontargeted analyses. The dietary intake of EPA and DHA can impact lipidomic profiles, which should be considered by lipidomic analysts. These results also suggest that comprehensive dietary assessments should be considered during the development of reference and quality control materials.

Tissue lipidomics is a rapidly advancing field in clinical and biomedical research that provides crucial information on the lipid-driven molecular mechanisms underlying physiological and pathological conditions. However, accurate MS-based analysis requires careful preanalytical handling due to the metabolic activity of tissue and analyte heterogeneity. Here, we introduce a robust tissue processing workflow with the pancreas as a model of a highly metabolically active organ. First, we evaluate lipid stability in porcine pancreatic tissue stored on ice, observing significant lysophospholipid formation after 60-120 min. Then, we compare sample handling using ice versus liquid nitrogen for both porcine and mouse pancreatic tissues, illustrating that processing temperature affects low-abundant lipid class levels, with liquid nitrogen providing better preservation. To enhance polar lipidome analysis, we optimize a hexane-methanol liquid-liquid extraction protocol and find that the addition of 2% (v/v) water to methanol yields the most effective recovery and reproducibility. Finally, the workflow is applied to mouse pancreatic tissue samples, enabling the identification of 209 polar lipid species across 10 classes, with 124 species quantified. Among these, hexosylceramides show clear sex-specific variation.

The relationship between early pregnancy lipid indicators and gestational diabetes mellitus (GDM) or pre-eclampsia (PE) remains incompletely elucidated. This prospective cohort study explored the associations between seven lipid indicators and GDM and PE among 32,411 pregnant participants. The results suggested that triglycerides (TGs), total cholesterols (TCs), and remnant cholesterols (RCs) were positively associated with both GDM and the composite outcome (GDM/PE). For GDM, compared with the lowest quartile, the highest quartile had odds ratios (ORs) of 1.646 (95% confidence interval [95% CI]: 1.363, 1.988) for TGs, 1.654 (95% CI: 1.241, 2.205) for TCs, and 1.396 (95% CI: 1.189, 1.640) for RCs. For GDM/PE, the corresponding ORs in the highest versus lowest quartile were 1.564 (95% CI: 1.302, 1.877) for TGs, 1.655 (95% CI: 1.253, 2.186) for TCs, and 1.379 (95% CI: 1.180, 1.612) for RCs. Non-HDL-C showed a negative association with GDM and GDM/PE, with ORs of 0.833 (95% CI: 0.758, 0.916) and 0.871 (95% CI: 0.795, 0.954), respectively. TG/HDL-C ratio was positively associated with PE, with an OR of 2.451 (95% CI: 1.369, 4.388). The OR values of the second and third quantiles of HDL-C for PE were 1.706 (95% CI: 1.301, 2.238) and 1.598 (95% CI: 1.170, 2.183), respectively. Nonlinear dose-response relationships were observed for most lipids with the outcomes. Additionally, early pregnancy TG, RC, and TG/HDL-C ratio partially mediated the effect of maternal age on all three outcomes (mediated proportion 2-7%). Non-HDL-C mediated the age-PE pathway (1%). This study simultaneously included multiple lipid parameters for systematic analysis, revealing the impact of dyslipidemia on pregnancy outcomes from a more comprehensive perspective and providing richer evidence for exploring related mechanisms and clinical assessment.

Endothelial-mesenchymal transition (EndMT) is crucial in atherosclerosis (AS) development, but its molecular mechanisms remain incompletely understood. TNFAIP3 is a crucial negative regulator that plays a central role in inflammatory responses and immune responses by inhibiting the NF-κB signaling pathway. This study aims to investigate the molecular mechanisms by which TNFAIP3 regulates EndMT and the progression of AS, as well as to elucidate the role of METTL3-mediated m6A modification in this process. Through both in vivo and in vitro assays, we analyzed the expression of TNFAIP3 in endothelial cells during AS and EndMT. In vitro, we inhibited TNFAIP3 expression in endothelial cells to observe its impact on EndMT. In vivo, we investigated the effects of endothelial cell-specific TNFAIP3 deficiency on EndMT and AS progression. Furthermore, we investigated whether this process is mediated through the NF-κB/Snail signaling pathway and observed the mitigating effect of inhibiting the NF-κB pathway on ox-LDL-induced EndMT. Finally, we studied the mechanism by which METTL3-mediated m6A modification regulates TNFAIP3 expression in endothelial cells. TNFAIP3 expression is downregulated in endothelial cells during AS and EndMT. Inhibition of TNFAIP3 expression in endothelial cells exacerbated EndMT induced by TGFβ or ox-LDL in vitro. Moreover, endothelial cell-specific deletion of TNFAIP3 increased the expression of mesenchymal markers and exacerbated AS progression. This process is mediated through the NF-κB/Snail signaling pathway. Suppression of the NF-κB pathway alleviated ox-LDL-induced EndMT. Additionally, the reduction in TNFAIP3 expression in endothelial cells is mediated by METTL3/YTHDF2-dependent m6A modification. In AS, the expression of METTL3 is upregulated in endothelial cells, accelerating the degradation of TNFAIP3 mRNA via YTHDF2-dependent m6A modification, thereby downregulating its expression levels. This process activates the NF-κB/Snail signaling pathway, which in turn promotes EndMT. This finding highlights the involvement of epigenetic mechanisms in AS, providing a theoretical basis and potential therapeutic targets for inhibiting EndMT and AS progression.

Phospholipase D2 (PLD2) plays critical roles in cellular signaling, membrane dynamics, and cancer progression. Oleate (OA) has been shown to activate PLD2 and promote triple-negative breast cancer (TNBC) cell migration, but the underlying molecular mechanisms remain poorly understood. Using confocal microscopy, lipid raft isolation, and S-acylation assays, we show that OA enhanced PLD2 S-acylation at Cys223 and Cys224, disrupting its lipid raft localization, and consequently increasing its colocalization with PIP₂-enriched microdomains. Furthermore, we identified PLD2 as a guanine nucleotide exchange factor (GEF) for Cdc42, with its GEF activity regulated by OA-dependent S-acylation and lipid raft dynamics. Mutation of the S-acylation sites or disruption of lipid rafts abolished PLD2-mediated Cdc42 activation and filopodia-like cell protrusion formation. These findings reveal a novel regulatory mechanism by which OA modulates PLD2 activity through S-acylation and membrane microdomain reorganization, providing new insights into the regulation of PLD2 in cell migration and signaling.

The mammary gland synthesizes and secretes nutrient-rich milk containing lactose, protein, and lipids, with the complex assortment of lipids providing more than half of the energy and bioactive factors that impact the growth and development of neonates. The birth of neonates initiates the lipogenic capacity of the mammary gland with upregulation in expression of lipogenic genes, including Stearoyl-CoA desaturase (Scd1). SCD1 plays a critical role in lipogenesis, catalyzing the conversion of saturated fatty acids to monounsaturated fatty acids. Previous studies of Scd1 knockout mice revealed that SCD1 impacts several metabolic processes in the liver and adipose tissue, including fat synthesis. However, the role of SCD1 in lactation is not fully understood. Our study aimed to determine the role of SCD1 in lactation and the effects of maternal knockout of Scd1 on the growth of the lactating neonates. We employed second-parity Scd1-deficient female mice (n = 7) that we compared with wild-type mice (n = 6). To determine lipid and metabolic alterations, mammary gland and milk samples were harvested on lactation day 10. Relative to wild-type mice, mammary gland weight, alveolar area, and milk glycerolipid content were reduced in lactating Scd1-deficient mice. Scd1 deficiency also diminished mammary gland biosynthetic metabolic pathways, such as glycerolipid and phospholipid synthesis, while enhancing catabolic pathways, such as fatty acid oxidation. Neonates nursed by Scd1-deficient mice exhibited lower body weights. These findings highlight the critical role of SCD1 in orchestrating metabolic adaptations during lactation to ensure adequate milk synthesis to support the rapidly growing neonates.

FAs play multifaceted roles in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review systematically summarizes current understanding of FA metabolism and its diverse implications in neurodegenerative diseases pathology. Short-chain FAs, primarily generated by gut microbiota, regulate neuroinflammation, gut-brain communication, and blood-brain barrier integrity via epigenetic modifications and immune modulation. Medium-chain FAs exhibit therapeutic potential by improving energy metabolism and neuromuscular function, particularly in amyotrophic lateral sclerosis models. Long-chain PUFAs, notably DHA and EPA, contribute to neuronal membrane integrity, synaptic plasticity, and antioxidant defense, mitigating oxidative stress and neuroinflammation. Conversely, saturated and certain n-6 FAs may exacerbate neurodegeneration through proinflammatory and oxidative pathways. Emerging evidence highlights FA involvement in key pathological processes such as lipid peroxidation, mitochondrial dysfunction, ferroptosis, and blood-brain barrier disruption. Therapeutically, targeted supplementation, dietary modification, microbiome manipulation, and advanced nanotechnology-based delivery systems are promising strategies. Nevertheless, precise therapeutic efficacy depends critically on disease stage, dosage, genetic background, and individual metabolic context. Integrating personalized medicine with precision nutritional strategies and novel drug-delivery platforms offers promising avenues to translate FA-based interventions into clinical practice, potentially improving patient outcomes in the aging global population.

Plasmalogens are structurally similar to phosphatidylcholine or phosphatidylethanolamine but differ at the Sn-1 position, containing a vinyl-ether instead of an ester bond. Reduced levels of plasmalogens in circulation or in cell membranes are associated with rare peroxisomal disorders, systemic disease, neurological impairment, cancer, and diseases of the heart, kidney, and liver. Roles for plasmalogens have been identified in lipid rafts, myelin, chlorolipids, bromolipids, hemostasis, cholesterol metabolism, and redox responses. The possible interconversion of plasmalogens into platelet-activating factor and the dysregulated activity of enzymes involved in the synthesis and catabolism of plasmalogens results in the reduced levels of these lipids during disease development. These enzymes also play dual roles in cell signaling, cellular respiratory homeostasis, innate immunity, inflammation, thrombosis, ferroptosis, autophagy, and neuron action potential. To further our understanding of plasmalogens as a biomarker and potential therapeutic, we have summarized clinical data on the role of these lipids in various diseases and the use of plasmalogens and their precursors in clinical trials. We also describe the complexities of plasmalogen synthesis and catabolism and detail aspects of these pathways in specific diseases that identify plasmalogens as a biomarker. Lastly, we summarize current and future research to better harness the effects of plasmalogens in the pathogenesis and treatment of systemic and/or organ-specific disease.