Journal of Lipid Research最新文献

{"title":"Associations between plasma 24(S)-Hydroxycholesterol and neuropsychological profile in Fragile X Syndrome.","authors":"Asma Laroui, Daniela Rojas, Sophie Bouhour, Mélodie Proteau-Lemieux, Luc Galarneau, Sérine Benachenhou, Armita Abolghasemi, Rosalie Plantefeve, Pierre-Luc Mallet, François Corbin, Jean-François Lepage, Artuela Çaku","doi":"10.1016/j.jlr.2025.100787","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100787","url":null,"abstract":"<p><p>Fragile X Syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 gene, characterized by low plasma cholesterol levels. Considering the essential role of brain cholesterol in signaling and synaptogenesis, it is important to screen for brain cholesterol abnormalities in FXS and explore their link with neuropsychological profiles. Brain cholesterol is synthesized in situ, and the excess is primarily converted to 24(S)-hydroxycholesterol (24(S)-OHC). 27-hydroxycholesterol (27-OHC) is the major cholesterol oxidation metabolite that crosses the blood-brain barrier from peripheral circulation into the brain Plasma levels of 24(S)-OHC and 27-OHC were quantified in FXS and control individuals. The FXS group underwent transcranial magnetic stimulation to evaluate corticospinal excitability and inhibition. The clinical profile was assessed using questionnaires evaluating specific symptoms related to autism, aberrant behaviors, and anxiety. Study results show a significant decrease in plasma levels of 24(S)-OHC in FXS as compared to controls (78.48 nM ± 20.90 vs 99.53 nM ± 32.30; p = 0.006). Moreover, a negative correlation was observed between plasma levels of 24(S)-OHC and Motor-Evoked Potential (r_s = -0.57; p = 0.05) in FXS. Similarly, a negative correlation was also found between plasma levels of 24(S)-OHC and the total score of the Social Communication Questionnaire (r_s = - 0.72; p = 0.002) and the Anxiety Depression and Mood Scale (r_s = - 0.61; p = 0.02). The 24(S)-OHC is associated with specific neurophysiological and behavioral characteristics in individuals with FXS. Larger studies are warranted to confirm the potential of 24(S)-OHC as a reliable biomarker for FXS.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100787"},"PeriodicalIF":5.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lecithin:Cholesterol Acyltransferase Binds a Discontinuous Binding Site on Adjacent Apolipoprotein A-I Belts in HDL.","authors":"Bethany Coleman, Shimpi Bedi, John H Hill, Jamie Morris, Kelly A Manthei, Rachel C Hart, Yi He, Amy S Shah, W Gray Jerome, Tomas Vaisar, Karin E Bornfeldt, Hyun Song, Jere P Segrest, Jay W Heinecke, Stephen G Aller, John J G Tesmer, W Sean Davidson","doi":"10.1016/j.jlr.2025.100786","DOIUrl":"10.1016/j.jlr.2025.100786","url":null,"abstract":"<p><p>Lecithin:cholesterol acyltransferase (LCAT) is a high-density lipoprotein (HDL) modifying protein that profoundly affects the composition and function of HDL subspecies. The cholesterol esterification activity of LCAT is dramatically increased by apolipoprotein A-I (APOA1) on HDL, but the mechanism remains unclear. Using site-directed mutagenesis, cross-linking, mass spectrometry, electron microscopy, protein engineering and molecular docking, we identified two LCAT binding sites formed by helices 4 and 6 from two antiparallel APOA1 molecules in HDL. Although the reciprocating APOA1 'belts' form two ostensibly symmetrical binding locations, LCAT can adopt distinct orientations at each site, as shown by our 9.8 Å cryoEM envelope. In one case, LCAT membrane binding domains align with the APOA1 belts and, in the other, the HDL phospholipids. By introducing disulfide bonds between the APOA1 helical domains, we demonstrated that LCAT does not require helical separation during its reaction cycle. This indicates that LCAT, anchored to APOA1 belts, accesses substrates and deposits products through interactions with the planar lipid surface. This model of the LCAT/APOA1 interaction provides insights into how LCAT and possibly other HDL-modifying factors engage the APOA1 scaffold, offering potential strategies to enhance LCAT activity in individuals with genetic defects.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100786"},"PeriodicalIF":5.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRP1 Immunotherapy Enhances Cardiomyocyte Respiration by Restricting Cholesteryl Ester Accumulation in Mitochondria.","authors":"A Benitez-Amaro, E Garcia, M T LaChica Lhoëst, A Polishchuk, I Zegri-Reiriz, D Vilades, J M Guerra, L Fernández-Del-Rio, S Mirabet, V Samouillan, O Shirihai, M Liesa, C Enrich, V Llorente-Cortés","doi":"10.1016/j.jlr.2025.100783","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100783","url":null,"abstract":"<p><p>Antibodies targeting the P3 sequence (Gly¹¹²⁷-Cys¹¹⁴⁰) of LRP1 (anti-P3 Abs) inhibit the interaction between ApoB100 in cholesteryl ester (CE)-enriched lipoproteins and the CR9 domain in LRP1, preventing intracellular CE accumulation induced by a high-fat high-cholesterol (HFHC) diet in cardiomyocytes. This study examines (i) whether HFHC induces cholesterol accumulation in mitochondria, and impacts cardiac bioenergetics, and (ii) the effectiveness of anti-P3 Abs in mitigating HFHC-induced mitochondrial alterations. Cardiac tissue was homogenized, and mitochondria was isolated through subcellular fractionation. Thin-layer chromatography (TLC) demonstrated that HFHC induced the accumulation of CE in cardiac mitochondria, and that this process was significantly reduced by anti-P3 antibodies. In line, transmission electron microscopy (TEM) studies revealed that morphological changes induced by HFHC in cardiomyocyte mitochondria were reversed, at least in part, by anti-P3 Abs. Additionally, anti-P3 antibodies promoted more extensive interactions between mitochondria and lipid droplets (LDs), accompanied by an increase in LD diameter and electrodensity in cardiomyocytes. Cardiac mitochondrial respiratory capacity assessed by Seahorse analysis showed that HFHC reduced CI/CIV and CII/CIV activity ratios, while anti-P3 Abs restored complex II/IV activity. In conclusion, by blocking CE uptake from lipoproteins, anti-P3 antibodies reduce CE accumulation in the cardiomyocyte mitochondria and LDs, enhance bioenergetically favorable mitocondria/LD interactions, and improve cardiomyocyte respiratory function in hypercholesterolemic rabbits. These findings highlight the therapeutic potential of anti-P3 Abs in metabolic diseases by limiting CE loading of mitocondria and LDs in the heart and restoring cardiac bioenergetics.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100783"},"PeriodicalIF":5.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein A1 deficiency increases Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Plaques in a Bim dependent manner.","authors":"Alexander S Qian, George E G Kluck, Pei Yu, Leticia Gonzalez, Elizabeth Balint, Bernardo L Trigatti","doi":"10.1016/j.jlr.2025.100782","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100782","url":null,"abstract":"<p><p>In advanced atherosclerotic lesions, macrophage apoptosis contributes to plaque progression and the formation of necrotic cores, rendering plaques vulnerable to rupture. The pro-apoptotic protein Bim plays a crucial role in mediating apoptosis in macrophages under prolonged endoplasmic reticulum (ER) stress. High-density lipoprotein (HDL) has been shown to suppress macrophage apoptosis induced by ER stressors. To investigate the impact of apolipoprotein A1 (ApoA1) deficiency, associated with reduced HDL levels, on necrotic core growth and plaque apoptosis, we introduced ApoA1 deficiency into low-density lipoprotein receptor (LDLR) knockout mice and fed them a high-fat diet for 10 weeks. ApoA1-deficient LDLR knockout mice developed advanced plaques characterized by large necrotic cores, increased apoptosis, and elevated Bim expression in macrophages within the plaques. To assess whether deletion of Bim could mitigate this development, mice underwent bone marrow transplantation with bone marrow from either Bim-deficient mice or from mice with a deletion of myeloid-derived Bim driven by LyzM-cre. Inhibiting Bim in all bone marrow-derived cells led to leukocytosis, reductions in plasma cholesterol and triglyceride levels, and decreased plaque apoptosis, necrotic core, and plaque sizes in ApoA1 and LDLR double-knockout mice but not in LDLR knockout mice. Likewise, conditional deletion of Bim in the myeloid compartment of ApoA1 and LDLR double-knockout mice also reduced apoptosis, necrotic core sizes, and plaque sizes, without inducing leukocytosis or lowering plasma cholesterol levels. These findings suggest that ApoA1 deficiency triggers apoptosis in myeloid cells through a Bim-dependent pathway, significantly contributing to the development of necrotic cores and the progression of atherosclerotic plaques.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100782"},"PeriodicalIF":5.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visualize neuronal membrane cholesterol with split- fluorescent protein tagged YDQA sensor.","authors":"Yi Xu, Saixuan Li, Yiran Xu, Xiaoqin Sun, Yuqing Wei, Yuejun Wang, Shuang Li, Yongqi Ji, Keyi Hu, Yuxia Xu, Cuiqing Zhu, Bin Lu, Dandan Wang","doi":"10.1016/j.jlr.2025.100781","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100781","url":null,"abstract":"<p><p>Cholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer's disease (AD). However, in vivo visualization of cholesterol has remained challenging, hindering a comprehensive understanding of AD pathology. In this study, we generated a new sensor combining the split-fluorescent protein tags with YDQA, a derivate of cholesterol-dependent cytolysin PFO. Through a series of validations in cell and C. elegans models, we demonstrate that the new sensor (name as sfPMcho) efficiently detects neuronal PM cholesterol. We further applied this sensor in 5X FAD and APOE KO mice models and revealed the cholesterol changes within neurons. PM cholesterol became sparse and locally aggregated in neuron bodies but significantly accumulated in nerve fibers. Collectively, this study provides a new tool for detecting neuronal PM cholesterol in vivo and uncovers cholesterol abnormalities in AD-related pathology at the cellular level. Further development based on this sensor or the similar strategy are to be expected.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100781"},"PeriodicalIF":5.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Lipidomics Reveals High Individuality and Sex Specificity of Circulatory Lipid Signatures: A Prospective Healthy Population Study.","authors":"Jessica Medina, Nicolas Goss, Gonçalo Dos Santos Correia, Rebecca Borreggine, Tony Teav, Zoltan Kutalik, Pedro Marques Vidal, Hector Gallart-Ayala, Julijana Ivanisevic","doi":"10.1016/j.jlr.2025.100780","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100780","url":null,"abstract":"<p><p>Lipid metabolism and circulatory lipid levels are tightly associated with the (cardio)metabolic health. Consequently, mass spectrometry (MS)-based lipidomics has emerged as a powerful phenotyping tool in epidemiological, human population, and in clinical intervention studies. However, ensuring high throughput and reproducible measurement of a wide panel of circulatory lipid species in large-scale studies poses a significant challenge. Here, we applied a recently developed quantitative LC-MS/MS lipidomics approach to a subset of 1086 fasted plasma samples belonging to apparently healthy participants from prospective Lausanne population study. This high-coverage and high-throughput HILIC-based methodology allowed for the robust measurement of 782 circulatory lipid species spanning 22 lipid classes and six orders of magnitude-wide concentration range. This was achieved by combining semi-automated sample preparation using a stable isotope dilution approach and the alternate analysis of NIST plasma reference material, as a quality control. Based on NIST QC analysis, median between-batch reproducibility was 8.5%, over the course of analysis of 13 independent batches comprising 1086 samples collected from 364 individuals at three time points. Importantly, the biological variability, per lipid species, was significantly higher than the batch-to-batch analytical variability. Furthermore, the significantly lower between-subject (compared to within-subject) variability, and unsupervised sample clustering demonstrated the high individuality and sex-specificity of circulatory lipidome. The most prominent sex differences were reported for sphingomyelins and ether-linked phospholipids present in significantly higher concentrations in female plasma. The high individuality and sex specificity of circulatory lipidome constitute important advantages for the application of lipidomics in next-generation metabolic health monitoring.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100780"},"PeriodicalIF":5.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High density lipoproteins and COVID-19: preparing the next pandemic.","authors":"Marie Laurine Apalama, Floran Begue, Sébastien Tanaka, Maxime Cournot, David Couret, Olivier Meilhac, Mohammad Ryadh Pokeerbux","doi":"10.1016/j.jlr.2025.100779","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100779","url":null,"abstract":"<p><p>High-density lipoproteins (HDLs) are heterogeneous particles with pleiotropic functions including anti-inflammatory and anti-infectious effects. In clinical studies, lower HDL-associated cholesterol (HDL-C) concentration has been associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity and mortality. A reduction in the number of HDL particles, particularly small ones has been observed with alterations in their protein and lipid composition impairing their functions. These observations have supported HDL supplementation with promising results in small preliminary studies. This review summarizes available evidence on these different aspects to better understand the two-way interaction between HDLs and Coronavirus disease 2019 (COVID-19) and guiding future HDL-based therapies for preparing the next pandemic.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100779"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential causal evidence for an ApoB-independent and HDL-related risk profile associated with coronary artery disease.","authors":"Linjun Ao, Diana van Heemst, J Wouter Jukema, Patrick C N Rensen, Ko Willems van Dijk, Raymond Noordam","doi":"10.1016/j.jlr.2025.100778","DOIUrl":"10.1016/j.jlr.2025.100778","url":null,"abstract":"<p><p>Plasma ¹H-NMR metabolomic measures have yielded significant insight into the pathophysiology of cardiometabolic disease, but their inter-related nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated ¹H-NMR metabolomic profiles with coronary artery disease (CAD) and ischemic stroke (IS). Principal component (PC) analysis was performed on 168 ¹H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve uncorrelated PCs, which were used in Cox-proportional hazard models. For each outcome, two-sample Mendelian randomization analyses were then conducted based on three nonoverlapping databases, followed by a meta-analysis. The first six PCs collectively explaining 88% of the total variance were identified. For CAD, results from Cox and Mendelian randomization analyses were generally directionally consistent. The pooled odds ratios (95% CI) for CAD per one-SD increase in genetically influenced PC1 and PC3 (both characterized by distinct apolipoprotein B [ApoB]-associated lipoprotein profiles) were 1.04 (1.03, 1.05) and 0.94 (0.93, 0.96), respectively. Besides, the pooled odds ratio (95% CI) for CAD per one-SD increase in genetically influenced PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 (1.03, 1.07). For IS, increases of PC3 and PC5 (characterized by increased amino acids) were associated with a lower risk and a higher risk, respectively. This study confirms associations of ApoB-associated lipoprotein profiles with CAD and IS, and highlights the possible existence of an ApoB-independent lipoprotein profile, characterized by a distinctive HDL subparticle distribution, driving CAD.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100778"},"PeriodicalIF":5.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of genetic markers related to hyper-HDL cholesterol on the prevalence of myocardial infarction: a KoGES study.","authors":"Sung-Bum Lee, Kyung-Won Hong, Byoungjin Park, Dong-Hyuk Jung","doi":"10.1016/j.jlr.2025.100777","DOIUrl":"10.1016/j.jlr.2025.100777","url":null,"abstract":"<p><p>Recent studies have shown that hyper-high-density lipoprotein cholesterol (HDL-C) is associated with cardiovascular disease risk and all-cause mortality, a phenomenon known as the HDL-C paradox. Several genes have been reported to show relationships between increased HDL-C and myocardial infarction (MI) risk. We investigated the genetic predisposition of lipid metabolism influencing MI. The study dataset was from the Korean Genome and Epidemiology cohort obtained from the National Biobank of Korea, with an initial population of 68,806 individuals. We categorized samples based on HDL-C levels into hypo-HDL-C (n = 25,884), normal-HDL-C (n = 41,117), and hyper-HDL-C groups (n = 1,805). We conducted genome-wide association studies for each group and the total sample. Significant associations were defined using genome-wide significant level and suggestive level. The lead SNP of each locus was selected for further interpretation. This analysis included 2,014 (2.6%) MI patients. Using multivariable logistic regression, we evaluated the association of 7,877 SNPs in nine loci. We identified six SNPs significantly related to both hypo- and hyper-HDL groups, one SNP associated with hyper-HDL, and six SNPs associated with hypo-HDL group. Additionally, we found three SNPs associated with MI prevalence in the hyper-HDL group, including one significant SNP and two suggestive SNPs. Contrary to the traditional view of HDL-C as protective, this study identified genetic variants that increase MI risk by more than six-fold. These SNPs could play a role as important markers for detecting MI in hyper-HDL cholesterol group.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100777"},"PeriodicalIF":5.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hexokinase 2 Promotes ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 in Sepsis-Induced Microglia Cells.","authors":"Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling","doi":"10.1016/j.jlr.2025.100776","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100776","url":null,"abstract":"<p><p>Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights of HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100776"},"PeriodicalIF":5.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}