Journal of Lipid Research最新文献

筛选
英文 中文
Highly tail-asymmetric lipids interdigitate and cause bidirectional ordering. 高度尾部不对称的脂质交叉并导致双向排序。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-04-04 DOI: 10.1016/j.jlr.2025.100797
Tugba N Ozturk, Thomas J Ferron, Wei He, Benjamin Schwarz, Thomas M Weiss, Nicholas O Fischer, Amy Rasley, Timothy S Carpenter, Catharine M Bosio, Helgi I Ingólfsson
{"title":"Highly tail-asymmetric lipids interdigitate and cause bidirectional ordering.","authors":"Tugba N Ozturk, Thomas J Ferron, Wei He, Benjamin Schwarz, Thomas M Weiss, Nicholas O Fischer, Amy Rasley, Timothy S Carpenter, Catharine M Bosio, Helgi I Ingólfsson","doi":"10.1016/j.jlr.2025.100797","DOIUrl":"10.1016/j.jlr.2025.100797","url":null,"abstract":"<p><p>Phospholipids form structurally and compositionally diverse membranes. A less studied type of compositional diversity involves phospholipid tail variety. Some phospholipids contain two acyl tails which differ in length. These tail-asymmetric lipids are shown to contribute to temperature sensitivity, oxygen adaptability, and membrane fluidity. Membranes of a highly virulent intracellular bacterium, Francisella tularensis, contain highly tail-asymmetric 1-lignoceroyl-2-decanoyl-sn-glycero-3-phosphatidylethanolamine (XJPE) lipids which were previously shown to inhibit inflammatory responses in host cells. XJPE tails have unusually high asymmetry, and how they contribute to membrane properties on a molecular level is unknown. Here, we use small angle X-ray scattering and molecular dynamics simulations to investigate how varying XJPE ratios alters properties of simple membranes. Our results demonstrate that at high concentration they promote liquid-to-gel transition in otherwise liquid membranes, while at low concentration they are tolerated well, minimally altering membrane properties. In liquid membranes, XJPE lipids dynamically adopt two main conformations; with the long tail extended into the opposing leaflet or bent-back residing in its own leaflet. When added to both leaflets XJPE primarily adopts an extended confirmation, while asymmetric addition results in more bent-back orientations. The former increases tail ordering and the latter decreases it. XJPE tails adopt different conformations that induce composition- and leaflet-dependent bidirectional effect on membrane fluidity and this suggests that Francisella tularensis could use tail asymmetry to facilitate vesicle fusion and destabilize host cells. The effect of tail-asymmetric lipids on complex membranes should be further investigated to reveal the regulatory roles of high tail asymmetry.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100797"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cardiomyopathy in a c.1528G>C Hadha mouse is associated with cardiac tissue lipotoxicity and altered cardiolipin species. C . 1528g >C Hadha小鼠的心肌病与心脏组织脂肪毒性和心磷脂种类改变有关。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-03-29 DOI: 10.1016/j.jlr.2025.100792
Chibuike Eke, Shannon Babcock, Garen Gaston, Gabriela Elizondo, Hak Chung, Ayah Asal, Kathryn C Chatfield, Genevieve C Sparagna, Andrea E DeBarber, William Packwood, Jonathan R Lindner, Melanie B Gillingham
{"title":"Cardiomyopathy in a c.1528G>C Hadha mouse is associated with cardiac tissue lipotoxicity and altered cardiolipin species.","authors":"Chibuike Eke, Shannon Babcock, Garen Gaston, Gabriela Elizondo, Hak Chung, Ayah Asal, Kathryn C Chatfield, Genevieve C Sparagna, Andrea E DeBarber, William Packwood, Jonathan R Lindner, Melanie B Gillingham","doi":"10.1016/j.jlr.2025.100792","DOIUrl":"10.1016/j.jlr.2025.100792","url":null,"abstract":"<p><p>Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a metabolic disorder caused by the loss of LCHAD enzymatic activity in the α-subunit of the trifunctional protein (TFPα), leading to impaired fatty acid oxidation (FAO). Patients with LCHADD often develop dilated cardiomyopathy. A previously unrecognized enzymatic function of TFPα as monolysocardiolipin acyltransferase (MLCL-AT) has been implicated in cardiolipin remodeling, crucial for mitochondrial cristae integrity. However, it remains unclear whether the common pathogenic variant c.1528G>C in HADHA impairs MLCL-AT activity in TFPα. In this study, we investigated whether cardiac cardiolipin profiles are altered in LCHADD and explored potential pathophysiological mechanisms, including heart lipid accumulation, changes in the cardiolipin synthesis pathway, and mitochondrial dynamics, utilizing a murine model of LCHADD carrying c.1528G>C variant that mimics the cardiomyopathy observed in humans. LCHADD mice developed eccentric hypertrophic cardiomyopathy from 3- to 12 months of age. 12-month-old LCHADD hearts exhibited altered cardiolipin profiles and increased oxidized cardiolipin. LCHADD hearts had higher lipid content, and the shift in fatty acid profile mirrored the shift in cardiolipin profile compared to wild-type controls, suggesting altered cardiolipin composition in LCHADD may be a reflection of accumulated lipids caused by lower FAO. No differential expression of cardiolipin synthesis and remodeling pathway enzymes was observed, suggesting minimal impact of the c.1528G>C variant on cardiolipin remodeling pathway. LCHADD hearts showed an altered ratio of OPA1 isoforms, and mitochondria with swelling and disorganized cristae were present. These findings suggest that altered fatty acid, cardiolipin profiles, and mitochondrial dynamics may contribute to LCHADD cardiomyopathy, warranting further studies.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100792"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis. 氧化LDL刺激pkm2介导的mtROS产生和吞噬。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-04-16 DOI: 10.1016/j.jlr.2025.100809
Jue Zhang, Jackie Chang, Vaya Chen, Mirza Ahmar Beg, Wenxin Huang, Lance Vick, Yaxin Wang, Heng Zhang, Erin Yttre, Ankan Gupta, Mark Castleberry, Ziyu Zhang, Wen Dai, Jieqing Zhu, Shan Song, Moua Yang, Ashley Kaye Brown, Zhen Xu, Yan-Qing Ma, Brian C Smith, Jacek Zielonka, James G Traylor, Cyrine Ben Dhaou, A Wayne Orr, Weiguo Cui, Yiliang Chen
{"title":"Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.","authors":"Jue Zhang, Jackie Chang, Vaya Chen, Mirza Ahmar Beg, Wenxin Huang, Lance Vick, Yaxin Wang, Heng Zhang, Erin Yttre, Ankan Gupta, Mark Castleberry, Ziyu Zhang, Wen Dai, Jieqing Zhu, Shan Song, Moua Yang, Ashley Kaye Brown, Zhen Xu, Yan-Qing Ma, Brian C Smith, Jacek Zielonka, James G Traylor, Cyrine Ben Dhaou, A Wayne Orr, Weiguo Cui, Yiliang Chen","doi":"10.1016/j.jlr.2025.100809","DOIUrl":"10.1016/j.jlr.2025.100809","url":null,"abstract":"<p><p>Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pretreated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100809"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lecithin:cholesterol acyltransferase binds a discontinuous binding site on adjacent apolipoprotein A-I belts in HDL. 卵磷脂:胆固醇酰基转移酶结合邻近载脂蛋白a - i带的不连续结合位点。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-03-25 DOI: 10.1016/j.jlr.2025.100786
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
{"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":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049944/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HDL meets triglyceride. 高密度脂蛋白与甘油三酯相遇。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-04-04 DOI: 10.1016/j.jlr.2025.100796
Tugce Akcan, Fredric B Kraemer
{"title":"HDL meets triglyceride.","authors":"Tugce Akcan, Fredric B Kraemer","doi":"10.1016/j.jlr.2025.100796","DOIUrl":"10.1016/j.jlr.2025.100796","url":null,"abstract":"<p><p>The study by Liu et al in this issue of the Journal of Lipid Research leverages data from the UK Biobank to explore the impact of HDL-TG on atherosclerotic cardiovascular disease risk. The investigators observed that elevated serum triglyceride levels were associated with reduced HDL particle diameter and with increased HDL-TG. Using observational and Mendelian randomization analyses, HDL-TG levels were independently associated with atherosclerotic cardiovascular disease risk even after adjusting for multiple confounders and other risk factors. The results emphasize the need for a broader evaluation of lipid parameters that extends beyond traditional measurements and suggest that incorporating metrics like HDL-TG could enhance risk stratification.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100796"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The EPA oxylipin, 12-HEPE, directly regulates human platelet activity. EPA氧脂素,12-HEPE,直接调节人血小板活性。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-04-16 DOI: 10.1016/j.jlr.2025.100807
Krista Goerger, Livia Stanger, Andrew Rickenberg, Anthony Nguyễn, Taekyu Lee, Theodore R Holman, Michael Holinstat
{"title":"The EPA oxylipin, 12-HEPE, directly regulates human platelet activity.","authors":"Krista Goerger, Livia Stanger, Andrew Rickenberg, Anthony Nguyễn, Taekyu Lee, Theodore R Holman, Michael Holinstat","doi":"10.1016/j.jlr.2025.100807","DOIUrl":"10.1016/j.jlr.2025.100807","url":null,"abstract":"<p><p>Arterial thrombosis, driven by platelet hyperactivity, is the underlying pathophysiology of most major cardiovascular events. Dietary fish oil supplementation containing ω-3 polyunsaturated fatty acids (PUFAs) elicits cardiovascular protection in at-risk patients. Studies have attributed the cardiovascular benefits of ω-3 PUFAs to eicosapentaenoic acid (EPA), the primary ω-3 PUFA present in fish oil supplements. However, the role of EPA in platelet activation remains unclear. This study aimed to evaluate whether the cardiovascular protection observed in individuals taking dietary supplements containing EPA is achieved by altering platelet function. Additionally, we investigated whether these effects are mediated through the 12-lipoxygenase (12-LOX)-derived oxidized lipid (oxylipin) metabolite of EPA, 12(S)-hydroxy-5Z,8Z,10E,14Z,17Z-eicosapentaenoic acid (12-HEPE). Human whole blood, platelet-rich plasma, and washed platelets were treated with EPA or 12-HEPE to assess their ability to regulate platelet activity. Both EPA and 12-HEPE inhibited agonist-stimulated platelet aggregation, and 12-HEPE was found to be the primary oxylipin produced by platelets in the presence of EPA. Furthermore, 12-HEPE more potently attenuated dense granule secretion, α-granule secretion, and integrin α<sub>IIb</sub>β<sub>3</sub> activation, in comparison to EPA. Interestingly, while EPA delayed thrombin-induced clot retraction and reduced platelet adhesion under flow, 12-HEPE did not affect these processes. Both EPA and 12-HEPE attenuated ex vivo thrombus formation; however, the same inhibitory concentrations did not alter coagulation parameters in thromboelastography. This study demonstrates that EPA and its 12-LOX metabolite, 12-HEPE, effectively inhibit platelet activation. These findings suggest the antiplatelet effects of EPA are regulated, in part, through 12-HEPE, advancing our understanding of the cardiovascular benefits of EPA.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100807"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor. 利用分光荧光蛋白标记的 YDQA 传感器可视化神经元膜胆固醇。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-03-19 DOI: 10.1016/j.jlr.2025.100781
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
{"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":"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 a similar strategy is to be expected.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100781"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147230/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Associations between plasma 24(S)-hydroxycholesterol and neuropsychological profile in fragile X syndrome. 血浆24(S)-羟胆固醇与脆性X综合征神经心理特征的关系
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-03-27 DOI: 10.1016/j.jlr.2025.100787
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
{"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":"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<sub>s</sub> = -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<sub>s</sub> = -0.72; P = 0.002) and the Anxiety Depression and Mood Scale (r<sub>s</sub> = -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":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12088753/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria. LRP1 免疫疗法通过限制线粒体中胆固醇酯的积累增强心肌细胞的呼吸作用
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-03-22 DOI: 10.1016/j.jlr.2025.100783
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
{"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":"10.1016/j.jlr.2025.100783","url":null,"abstract":"<p><p>Antibodies (Abs) targeting the P3 sequence (Gly<sup>1127</sup>-Cys<sup>1140</sup>) of LDL receptor-related protein 1 (anti-P3 Abs) inhibit the interaction between ApoB100 in cholesteryl ester (CE)-enriched lipoproteins and the CR9 domain in LDL receptor-related protein 1, 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 were isolated through subcellular fractionation. Thin layer chromatography demonstrated that HFHC induced the accumulation of CE in cardiac mitochondria, and that this process was significantly reduced by anti-P3 Abs. In line, transmission electron microscopy studies revealed that morphological changes induced by HFHC in cardiomyocyte mitochondria were reversed, at least in part, by anti-P3 Abs. Additionally, anti-P3 Abs 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 Abs reduce CE accumulation in the cardiomyocyte mitochondria and LDs, enhance bioenergetically favorable mitochondria/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 mitochondria 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":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051619/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impaired ApoB secretion triggers enhanced secretion of ApoE to maintain triglyceride homeostasis in hepatoma cells. ApoB分泌受损触发ApoE分泌增强以维持肝癌细胞甘油三酯稳态。
IF 5 2区 医学
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-04-01 DOI: 10.1016/j.jlr.2025.100795
Kotomi Shinozaki, Tomoko Honda, Kenzaburo Yamaji, Emi Nishijima, Ikuyo Ichi, Daisuke Yamane
{"title":"Impaired ApoB secretion triggers enhanced secretion of ApoE to maintain triglyceride homeostasis in hepatoma cells.","authors":"Kotomi Shinozaki, Tomoko Honda, Kenzaburo Yamaji, Emi Nishijima, Ikuyo Ichi, Daisuke Yamane","doi":"10.1016/j.jlr.2025.100795","DOIUrl":"10.1016/j.jlr.2025.100795","url":null,"abstract":"<p><p>Apolipoprotein B (ApoB) is essential for the assembly and secretion of triglyceride (TG)-rich VLDL particles, and its dysfunction is linked to metabolic disorders, including dyslipidemia and liver steatosis. However, less attention has been paid to whether and how other apolipoproteins play redundant or compensatory roles when the ApoB function is compromised. Here, we investigated the effects of microsomal triglyceride transfer protein (MTP), which mediates lipidation of nascent ApoB, on ApoE function. We observed a paradoxical increase in ApoE secretion resulting from increased expression in MTP inhibitor (MTPi)-treated human hepatoma cells. This phenotype was recapitulated in APOB-knockout cells and was associated with impaired ApoB secretion. While MTP-dependent transfer of neutral lipids is dispensable for ApoE secretion, TG biosynthesis, redundantly catalyzed by DGAT1 and DGAT2, is required for efficient ApoE secretion in hepatoma cells. ApoE colocalizes with lipid droplets near the Golgi apparatus and mediates TG export in an ApoB-independent fashion. We found that simultaneous inhibition of both ApoE and ApoB, but not inhibition of either alone, led to TG accumulation in hepatoma cells, indicating that both proteins function redundantly to control TG content. Validation studies in primary human hepatocytes (PHHs) demonstrated DGAT2-dependent secretion of ApoE. While MTPi treatment did not elevate ApoE secretion, it induced increased sialylation of ApoE in the supernatants of PHHs. These results show that enhanced ApoE secretion compensates for the impaired ApoB function to maintain the lipid homeostasis, providing an alternative route to modulate lipid turnover in hepatoma cells.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100795"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信