Journal of Lipid Research最新文献

{"title":"Lipoprotein Dynamics in Neuromyelitis Optica Spectrum Disorder.","authors":"Tsai-Wei Liu, Mei-Ling Cheng, Chiung-Mei Chen, Long-Sun Ro, Kuo-Hsuan Chang","doi":"10.1016/j.jlr.2025.100864","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100864","url":null,"abstract":"<p><p>Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disease caused by aquaporin-4 (AQP4) IgG antibodies, which damage astrocytes and trigger inflammation. Although altered lipid profiles have been observed in various neuroinflammatory diseases, the role of dyslipidemia in NMOSD disease activity remains poorly understood. In this study, we analyzed plasma lipoprotein profiles in 40 patients with NMOSD during relapses, 35 patients with multiple sclerosis (MS) during relapses, and 41 age- and sex-matched healthy controls (HCs). Among 112 lipoprotein components, 38 showed significant alterations in NMOSD patients compared to both MS patients and HCs. These components exhibited consistently lower levels during relapses. Receiver operating characteristic (ROC) analysis identified total apolipoprotein-A2 (Apo-A2; AUC = 0.808), HDL-3-Apo-A2 (AUC = 0.806), HDL-Apo-A2 (AUC = 0.798), VLDL-2-phospholipids (AUC = 0.774), VLDL-3-phospholipids (AUC = 0.769), and VLDL-3-triglycerides (AUC = 0.770) as robust biomarkers for distinguishing NMOSD from HCs, while VLDL-3-phospholipids (AUC = 0.791) and HDL-3-Apo-A2 (AUC = 0.752) effectively differentiated NMOSD from MS. Importantly, HDL-4-Apo-A2 levels negatively correlated with Expanded Disability Status Scale (EDSS) scores (r = -0.321, P = 0.043) and spinal cord lesion length (r = -0.391, P = 0.013) in NMOSD patients. Among 22 NMOSD patients evaluated longitudinally, 36 of the 38 dysregulated lipoprotein components return to normal levels during remission. This study represents the first comprehensive lipidomic analysis in NMOSD, revealing distinct dyslipidemia patterns associated with disease activity and highlighting the potential of lipoprotein profiling as a non-invasive prognostic biomarker.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100864"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698834","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":"Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer's disease and involves APOE4.","authors":"Carla Borràs, Marina Canyelles, David Santos, Noemí Rotllan, Estefanía Núñez, Jesús Vázquez, Daniel Maspoch, Mary Cano-Sarabia, Qi Zhao, Maria Carmona-Iragui, Sònia Sirisi, Alberto Lleó, Juan Fortea, Daniel Alcolea, Francisco Blanco-Vaca, Joan Carles Escolà-Gil, Mireia Tondo","doi":"10.1016/j.jlr.2025.100865","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100865","url":null,"abstract":"<p><p>In the central nervous system, apolipoprotein (APO)E-containing lipoprotein particles mediate the transport of glial-derived cholesterol to neurons, which is essential for neuronal membrane remodeling and maintenance of the myelin sheath. We aimed to examine cholesterol transport via lipoprotein particles in cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients compared to control individuals. Additionally, we explored the ability of reconstituted HDL containing different APOE isoforms to regulate cholesterol transport. We evaluated the capacity of CSF lipoprotein particles to facilitate radiolabeled unesterified cholesterol efflux from A172 human glioblastoma astrocytes and to deliver cholesterol to SH-SY5Y human neuronal cells. The CSF lipoprotein proteome was analyzed by LC-MS/MS. Reconstituted HDL nanoparticles were prepared by combining phospholipids and cholesterol with human APOE3 or APOE4, followed by radiolabeling with unesterified cholesterol. Our results showed that cholesterol efflux from astrocytes to CSF were similar between AD patients and controls, both under baseline conditions and after activation of ABCA1 and ABCG1. However, CSF lipoprotein-mediated neuronal cholesterol uptake was significantly reduced in the AD group. LC-MS/MS analysis identified 239 proteins associated with CSF lipoproteins in both groups, with no major alterations in proteins linked to cholesterol metabolism. However, 27 proteins involved in non-cholesterol-related processes were differentially expressed. Notably, synthetic reconstituted HDL particles containing APOE4 exhibited reduced capacity to deliver cholesterol to neurons compared to those with APOE3. These findings indicate that CSF lipoproteins from patients with AD demonstrate impaired cholesterol delivery to neurons. Our study highlights APOE4 as a critical contributor to abnormal neuronal cholesterol uptake in AD pathophysiology.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100865"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698830","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":"HBV-miR-3 induces hepatic cholesterol accumulation by targeting ABCA1: evidence for potential benefits of statin usage.","authors":"Shruti Chowdhari, Auroni Deep, Belal Ahmad, Jasmine Samal, Ekta Gupta, Perumal Vivekanandan","doi":"10.1016/j.jlr.2025.100866","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100866","url":null,"abstract":"<p><p>The cellular targets of hepatitis B virus (HBV)-encoded miRNAs remain poorly understood. The evolutionary conservation of HBV-miR-3 across HBV genotypes suggests its potential functional importance. Transcriptome profiling of HBV-miR-3 expressing hepatocytes demonstrates differential expression of several genes associated with lipid metabolic processes. The cholesterol efflux regulator gene ABCA1 was found to be down-regulated in our microarray data and in GEO datasets from HBV infected liver. We validated ABCA1 as a bonafide target of HBV-miR-3. HBV-miR-3-mediated suppression of ABCA1 led to increased cholesterol and lipid droplet accumulation in addition to increased proliferation and colony formation in hepatocyte cell lines. Interestingly, widely prescribed cholesterol-lowering drugs (simvastatin, atorvastatin and fluvastatin) could inhibit pro-oncogenic effects of HBV-miR-3. HBV-miR-3 expression was detectable in all liver biopsies (n=20) from chronic HBV (CHBV) patients. Patients with high intrahepatic HBV loads had higher levels of HBV-miR-3, suggesting that the virus-encoded miRNA levels correlate with virus replication. Patients with high HBV-miR-3 expression had significantly lower ABCA1 transcript levels in the liver. Hepatic steatosis was more frequently observed in biopsies of patients with high intrahepatic HBV-miR-3 levels compared to those with low HBV-miR-3 levels (71% vs 53%), although this was not statistically significant. Taken together, our findings support the notion that HBV-miR-3-mediated suppression of ABCA1 contributes to dysregulation of lipid metabolism in CHBV infection. In sum, HBV-miR-3 may represent the 'missing link' between CHBV and altered lipid metabolism in hepatocytes. Statin-mediated inhibition of HBV-miR-3-induced intrahepatic lipid accumulation and cell proliferation has potential clinical utility and merits further investigation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100866"},"PeriodicalIF":5.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698831","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":"Arachidonoyl-carnitine and arachidonoyl-coenzyme A are suitable substrates for mammalian ALOX isoforms.","authors":"Xin Chen, Sahanawaz Parvez, Hannah F Wiegand, Liuhui Wu, Sabine Stehling, Astrid Borchert, Junlin Yang, Polamarasetty Aparoy, Hartmut Kuhn","doi":"10.1016/j.jlr.2025.100861","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100861","url":null,"abstract":"<p><p>Lipoxygenases (ALOX) convert free polyenoic fatty acids to bioactive mediators, which induce phenotypic alterations in target cells. However, the intracellular concentrations of free fatty acids are very low since these compounds are either rapidly esterified with coenzyme-A. The acyl-CoA esters are subsequently used for re-acylation via the Lands cycle or they are trans-esterified to acyl carnitines for mitochondrial import. Whether acyl carnitines and acyl-CoA derivatives might also serve as ALOX substrates has not been explored. In the present study, we prepared six different wildtype mammalian ALOX-isoforms and a selected enzyme mutant, incubated the recombinant proteins in vitro with free arachidonic acid, arachidonoyl-carnitine and arachidonoyl-coenzyme A and quantified the amounts of primary oxygenation products. We found that for most ALOX-isoforms arachidonoyl-carnitine was oxygenated with a similar rate as free arachidonic acid and that the chemical structures of the primary oxygenation products were identical. In contrast, arachidonoyl-coenzyme A was oxygenated with a 3-5-fold lower rate but here again highly specific patterns of primary oxygenation products were formed. In silico docking studies and molecular dynamics simulations suggested that free arachidonic acid and arachidonoyl-carnitine are similarly aligned at the active site of rabbit ALOX15 but binding of arachidonoyl-coenzyme A was sterically hindered because of the bulkiness of the CoA moiety. Taken together, our data indicate that acyl carnitines and fatty acid coenzyme A esters are suitable lipoxygenase substrates and that these compounds are oxygenated to isoform-specific patterns of primary oxygenation products.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100861"},"PeriodicalIF":5.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667813","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":"In Memoriam: Scott M. Grundy (1933-2025).","authors":"Gloria Lena Vega, Jay D Horton, Henry N Ginsberg, Paul Nestel","doi":"10.1016/j.jlr.2025.100852","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100852","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 7","pages":"100852"},"PeriodicalIF":5.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659416","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":"Integrated lipidomic and proteomic profiling reveals metabolic network disruption by SARS-CoV-2 variants.","authors":"Scotland E Farley, Jennifer E Kyle, Helene Jahn, Lisa M Bramer, Paul D Piehowski, Athena A Shepmoes, Brooke Ld Kaiser, Sarai M Williams, Josie G Eder, Carsten Schultz, Fikadu G Tafesse","doi":"10.1016/j.jlr.2025.100860","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100860","url":null,"abstract":"<p><p>The rapid evolution of SARS-CoV-2 has produced myriad viral strains with increasing transmissibility and capacity for immune evasion. While effective vaccination campaigns have reduced the fatalities associated with SARS-CoV-2, infections continue, and a detailed understanding of how this virus manipulates host biochemical pathways remains elusive. We asked both whether the patterns of host lipid rewiring remained consistent across variants and whether the changes in the abundance of lipid classes are related to changes in the expression of the enzymes involved in their biosynthesis. We compared global nontargeted lipidomics on A549-ACE2 cells infected with the delta variant (B.1.617.2), or the omicron (B.1.1.529) variant to our previous results of global nontargeted lipidomics on A549-ACE2 cells infected with the original WA1 strain, and further performed quantitative proteomics to assess changes in the host proteome. We found that metabolic rewiring, both on the lipid and the enzymatic level, is remarkably consistent across all three variants. We further mapped changes in the expression of host metabolic enzymes, linking enzyme expression to alterations in the abundance of specific lipids during infection. This analysis identified key proteins related to virus-mediated changes in lipid abundance, including fatty acid synthase (FASN), lysosomal acid lipase (LIPA), and ORMDL, a regulator of sphingolipid biosynthesis. These integrated lipidomic and proteomic experiments shed light on the importance of the complex network of host metabolism networks that support SARS-CoV-2 infection, and suggest that lipid metabolism may be a promising avenue for uncovering conserved therapeutic targets.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100860"},"PeriodicalIF":5.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637233","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":"Effects of Fasting on HDL Particle Function and Size Distribution.","authors":"Joanne Agus, Angela M Zivkovic","doi":"10.1016/j.jlr.2025.100859","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100859","url":null,"abstract":"<p><p>The effects of fasting on high-density lipoprotein (HDL) particles remain an area of ongoing investigation. This narrative review examines the impact of various fasting regimens, including intermittent fasting (IF) and continuous fasting (CF), on HDL cholesterol (HDL-C), particle size distribution, and concentration. Current evidence on fasting's influence on HDL particles is limited and inconsistent, particularly in IF studies, where variability in HDL metrics, recruitment bias, and confounding factors-such as weight loss as a primary study goal-complicate interpretation. While some CF studies suggest a mild trend toward decreased HDL-C and alterations in HDL particle size distribution, the overall health implications of these changes remain unclear. Further research is needed to provide a more comprehensive understanding of how fasting affects HDL particles and their broader implication for health and disease.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100859"},"PeriodicalIF":5.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584160","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 lipoprotein attenuates lipopolysaccharide-induced IL-1β activation via scavenger receptor class B type 1.","authors":"Haoyu Deng, Wan Yi Liang, Leqi Chen, Kate Huang, Rylan Mccallum, Patrick C N Rensen, John H Boyd, Mark Trinder, Liam R Brunham","doi":"10.1016/j.jlr.2025.100858","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100858","url":null,"abstract":"<p><p>Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100858"},"PeriodicalIF":5.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575660","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":"Fatty acid nitroalkenes regulate intestinal lipid absorption.","authors":"Francisco J Schopfer, Lihong Teng, Ahssan Sekandari, Ese S Ekhator, Alison B Kohan, Bruce A Freeman, Marco Fazzari","doi":"10.1016/j.jlr.2025.100855","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100855","url":null,"abstract":"<p><p>Fatty acid nitroalkenes (NO₂-FA) are tissue-protective and anti-inflammatory endogenous lipid mediators. A unique electrophilic character promotes reversible reactions with protein thiols, influencing key cellular functions. Given their generation during digestion and therapeutic potential, understanding the mechanisms and impact of NO₂-FA absorption and distribution is crucial. We investigated the intestinal absorption of orally administered 10-nitro-octadec-9-enoic acid (10-NO₂-OA) in male and female rats, using a portal vein- and mesenteric lymph duct-cannulated conscious model. There were no sex-related differences in the plasma distribution of 10-NO₂-OA and its inactive metabolite 10-nitro-octadecanoic acid (10-NO₂-SA). 10-NO₂-OA was extensively esterified into triglycerides at concentrations ∼60 times greater than the free acid. Duodenal administration showed that 10-NO₂-OA is primarily incorporated into chylomicron triglycerides (TAG) and transported via the lymphatic system, bypassing initial hepatic metabolism. Notably, 10-NO₂-OA significantly reduced lymph flow, chylomicron secretion, and impacted lymphatic TAG profile and transit. Assessment of intestinal TAG uptake by ³H-triolein tracing in mice showed that 10-NO₂-OA significantly reduced dietary fat absorption (∼75-50%), as evidenced by reduced radioactive levels in plasma w/o an endothelial lipase inhibitor. Quantitation of radioactivity distribution along the gastrointestinal tract showed a trend to greater lipid incorporation into the mucosa. Overall, these results show that NO₂-FA are primarily absorbed and transported through the lymphatic system as esterified TAG species, undergoing initial metabolism in enterocytes regardless of sex, with an unexpected impact on intestinal fatty acid uptake. These findings reveal novel actions of both endogenously-formed and orally-administered electrophilic NO₂-FA in modulating inflammatory and metabolic syndrome-related pathologies.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100855"},"PeriodicalIF":5.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567525","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":"Repurposing Daclatasvir for MASLD Therapy - A Promising Step Forward with Challenges Ahead.","authors":"Carlos Jose Pirola","doi":"10.1016/j.jlr.2025.100857","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100857","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100857"},"PeriodicalIF":5.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567527","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}