Journal of Lipid Research最新文献

Macrophage signaling and function are regulated by distinct sterol biochemistries. 巨噬细胞的信号和功能受不同的固醇生物化学调节。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-05-07 DOI: 10.1016/j.jlr.2026.101054

Jazmine D W Yaeger, Bijaya Pradhan, Jason G Kerkvliet, Amelia G Lawver, Sonali Sengupta, Natalie W Thiex, Kevin R Francis

{"title":"Macrophage signaling and function are regulated by distinct sterol biochemistries.","authors":"Jazmine D W Yaeger, Bijaya Pradhan, Jason G Kerkvliet, Amelia G Lawver, Sonali Sengupta, Natalie W Thiex, Kevin R Francis","doi":"10.1016/j.jlr.2026.101054","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101054","url":null,"abstract":"Membranes require continuous reorganization of lipid components, including sterols, to dynamically alter their rigidity to deform and bend during scission events which occur during fundamental cellular functions such as endocytosis. While diseases of cholesterol biosynthesis result in reduced cellular cholesterol and accumulation of precursor sterols, limited studies have addressed the intracellular consequences of disease-associated sterol changes on the ability of eukaryotic cellular membranes to function and signal normally. Here, we utilized bone marrow-derived macrophages (BMDMs) to investigate how altered sterol content impacts macrophage signaling and membrane function. Through pharmacological inhibition of cholesterol biosynthetic enzymes, reduced cholesterol and increased levels of disease-associated sterol intermediates coincided with reduced expression of cell surface proteins and impaired macropinocytosis. Macropinocytic activity was sensitive to both reduced plasma membrane cholesterol and sterols containing functional groups substituted for the C3 hydroxyl group. Transcriptomic analyses of cholesterol-inhibited BMDMs revealed alterations in immune and chemokine signaling pathways. Decreased cholesterol was also associated with dysregulated vesicular sorting pathways and elevated expression of endosomal/lysosomal markers. Disrupted endosome expression and impaired macropinocytosis were also observed in BMDMs from mouse models of the cholesterol biosynthesis disorder Smith-Lemli-Opitz syndrome (SLOS). Our findings detail an important connection between sterol imbalance, membrane dynamics, and immune cell function.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101054"},"PeriodicalIF":4.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864185","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}

引用次数: 0

AMPK in charge: Aerobic Glycolysis Programs Unilocularity in Adipocytes. AMPK负责：脂肪细胞单细胞有氧糖酵解程序。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-05-04 DOI: 10.1016/j.jlr.2026.101052

Kast D J

引用次数: 0

HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation. HIV-1 tat诱导的VAPB破坏引发了一系列细胞器衰竭，最终导致神经元脂质积累。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-05-04 DOI: 10.1016/j.jlr.2026.101053

Maryline Santerre, Sterling P Arjona, Kathy Q Cai, Natalia Shcherbik, Bassel E Sawaya

{"title":"HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation.","authors":"Maryline Santerre, Sterling P Arjona, Kathy Q Cai, Natalia Shcherbik, Bassel E Sawaya","doi":"10.1016/j.jlr.2026.101053","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101053","url":null,"abstract":"People living with HIV develop persistent neurocognitive impairment despite viral suppression through incompletely defined mechanisms. HIV-1 Tat disrupts VAPB-PTPIP51 coupling at mitochondria-associated ER membranes via PTPIP51 tyrosine phosphorylation, causing VAPB relocalization away from MAMs, a causal mechanism established in our prior work. Here, we define the downstream metabolic consequences and establish VAPB as the critical determinant of neuronal lipid pathology. Lipidomic profiling identified triglycerides as the dominant altered species, comprising polyunsaturated forms normally destined for membrane synthesis or mitochondrial oxidation, consistent with membrane catabolism rather than de novo lipogenesis. Targeted metabolomics revealed bioenergetic collapse consistent with impaired mitochondrial oxidative function. The resulting lipid imbalance, including lipid droplet accumulation, produced secondary organellar dysfunction, including Golgi dispersal and ER stress. Critically, Tat failed to induce lipid droplet accumulation in shRNA-VAPB cells, while PTPIP51 silencing had no such protective effect, establishing that VAPB relocalization is the obligate trigger. Guanosine supplementation reduced lipid droplet accumulation, suggesting a link to bioenergetic failure that warrants further investigation. In postmortem HIV-infected frontal cortex, VAPB was paradoxically elevated yet correlated with worsening dementia severity, consistent with transcriptional upregulation that cannot overcome post-translational blockade of VAPB-MAM localization. The polyunsaturated triglycerides, depleted plasmalogens, and elevated ceramides documented here closely parallel lipid signatures reported in PLWH with cerebrovascular complications, implicating Tat-driven lipid dysregulation as a candidate mechanism for the incompletely explained elevation in stroke risk in this population.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101053"},"PeriodicalIF":4.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839003","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}

引用次数: 0

Unveiling Novel Macrophage-Specific Biomarkers in MASH through Single-Cell Sequencing for Diagnostic Modeling. 揭示新的巨噬细胞特异性生物标志物在MASH通过单细胞测序诊断模型。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-28 DOI: 10.1016/j.jlr.2026.101048

Tingting Wang, Xiayan Zhu, Yiying Zhang, Lihuang Su, Tongtong Pan

{"title":"Unveiling Novel Macrophage-Specific Biomarkers in MASH through Single-Cell Sequencing for Diagnostic Modeling.","authors":"Tingting Wang, Xiayan Zhu, Yiying Zhang, Lihuang Su, Tongtong Pan","doi":"10.1016/j.jlr.2026.101048","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101048","url":null,"abstract":"Macrophages are pivotal in metabolic dysfunction-associated steatohepatitis (MASH) progression, yet their specific markers remain elusive. To address this, we employed an integrated bioinformatics strategy, combining single-cell and bulk transcriptomic data from human MASH livers, to identify macrophage-related differentially expressed genes (Mφ-DEGs). We pinpointed five core Mφ-DEGs- FRMD4B, PTK2B, CPM, SPTLC2, and EPB41L2-that were predominantly expressed in macrophages, with enrichment within pro-fibrotic M2 subsets. A diagnostic model constructed from these genes demonstrated high accuracy (area under the curve = 0.9865) and was robustly validated in an independent cohort. In human and murine MASH samples, FRMD4B and PTK2B were consistently downregulated, whereas CPM, SPTLC2, and EPB41L2 were upregulated. Protein-level validation by immunohistochemistry and immunofluorescence confirmed these expression patterns in human and mouse livers, and in polarized THP-1-derived macrophages. Mendelian randomization analysis identified CPM as a significant causal protective factor, suggesting its upregulation may represent a compensatory response. These genes correlated with altered immune cell infiltration (e.g., T follicular helper and regulatory cells) and were enriched in key MASH pathways, including fatty acid metabolism, sphingolipid signaling, and transforming growth factor beta/PI3K-Akt. Our findings were further corroborated through a multi-level validation framework encompassing clinical samples, a murine MASH model, and in vitro macrophage cultures. This study defines a robust macrophage-specific gene signature for MASH diagnosis and provides genetic evidence for a causal, protective role of CPM. The pronounced enrichment of these genes in M2 macrophages underscores their critical contribution to immunometabolic dysregulation, offering novel insights into MASH pathogenesis and potential diagnostic and therapeutic targets.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101048"},"PeriodicalIF":4.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816320","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}

引用次数: 0

Direct Lp(a)-C Measurements Provide Evidence for Apo(a) Isoform-Dependent Cholesterol Composition of Lp(a). 直接脂蛋白(a)-C测量为脂蛋白(a)的载脂蛋白(a)同型依赖性胆固醇组成提供了证据。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-27 DOI: 10.1016/j.jlr.2026.101051

Sotirios Tsimikas, Santica M Marcovina

{"title":"Direct Lp(a)-C Measurements Provide Evidence for Apo(a) Isoform-Dependent Cholesterol Composition of Lp(a).","authors":"Sotirios Tsimikas, Santica M Marcovina","doi":"10.1016/j.jlr.2026.101051","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101051","url":null,"abstract":"Lipoprotein(a) [Lp(a)] carries cholesterol [Lp(a)-C], yet the cholesterol composition of Lp(a) particles and its relationship to apolipoprotein(a) [apo(a)] isoform size remains incompletely defined. Prior estimates of Lp(a)-C have relied on fixed-percentage assumptions rather than direct biochemical measurement, limiting insight into particle-level heterogeneity. We developed a direct immunocapture assay using the monoclonal antibody LPA4 to quantify Lp(a)-C in plasma and applied it to 94 individuals spanning a wide range of Lp(a) concentrations and apo(a) isoform sizes. Lp(a)-C was strongly correlated with Lp(a) molar concentration (R = 0.925, P < 0.001) and inversely associated with apo(a) isoform size (R = -0.745, P < 0.001). Across tertiles of the predominant apo(a) isoform size, smaller isoforms (12-17 KIV repeats) had higher Lp(a)-C (8.3 ± 4.3 mg/dL; 11.0 ± 3.4%), mid-range isoforms (18-23 KIV) were intermediate (5.0 ± 3.2 mg/dL), whereas larger isoforms (>24 KIV) showed lower Lp(a)-C (3.0 ± 1.5 mg/dL) (P < 0.001). In contrast, particle-normalized metrics demonstrated the opposite pattern: both the Lp(a)-C/Lp(a) molar ratio and Lp(a)-C/Lp(a)-apoB mass ratio increased progressively with apo(a) isoform size (P < 0.001), indicating greater cholesterol content per Lp(a) particle among larger isoforms. These findings demonstrate a dissociation between circulating Lp(a)-C concentration, which primarily reflects particle number, and cholesterol content per particle, which varies systematically with apo(a) isoform size. Direct measurement of Lp(a)-C identifies compositional heterogeneity not captured by conventional estimation methods and may provide a framework for future studies of isoform-dependent variation in Lp(a) structure and function.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101051"},"PeriodicalIF":4.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773796","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}

引用次数: 0

Effects of fenofibrate on angiopoietin-like 3/4/8 proteins and apolipoprotein A5. 非诺贝特对血管生成素样3/4/8蛋白和载脂蛋白A5的影响。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-27 DOI: 10.1016/j.jlr.2026.101050

Ye Yang, Sydney Smith, Yan Q Chen, Hongxia Li, Eugene Y Zhen, John H Sloan, Robert W Siegel, Yuewei Qian, Yi Wen, Hyesoo Jung, Julia L Scheithauer, Sander Kersten, Stephen G Young, Robert J Konrad

{"title":"Effects of fenofibrate on angiopoietin-like 3/4/8 proteins and apolipoprotein A5.","authors":"Ye Yang, Sydney Smith, Yan Q Chen, Hongxia Li, Eugene Y Zhen, John H Sloan, Robert W Siegel, Yuewei Qian, Yi Wen, Hyesoo Jung, Julia L Scheithauer, Sander Kersten, Stephen G Young, Robert J Konrad","doi":"10.1016/j.jlr.2026.101050","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101050","url":null,"abstract":"Fenofibrate and other fibrates are peroxisome proliferator-activated receptor alpha (PPARα) agonists that are used to lower plasma triglyceride (TG) levels. Although fibrates are effective in decreasing TG, their ability to reduce adverse cardiovascular events and cardiovascular mortality in clinical trials has been disappointing. PPARα agonists influence the expression of dozens of genes, but the mechanisms by which they lower TG levels are incompletely understood. Apolipoprotein A5 (APOA5) and angiopoietin-like proteins 3, 4, and 8 (ANGPTL3/4/8) are important regulators of intravascular TG metabolism. To explore if their regulation might explain the TG-lowering effect of fibrates, we examined the impact of fenofibrate on the expression of APOA5 and the ANGPTL3/4/8 proteins in mice and humans. In wild-type mice, fenofibrate reduced plasma TG levels, increased Angptl4 and Angptl3 transcripts in the liver, and reduced Angptl8 and Apoa5 transcripts. Fenofibrate also decreased plasma APOA5 levels and increased levels of ANGPTL3, ANGPTL3/8, ANGPTL4/8, and the C-terminal domain of ANGPTL4 (CD-ANGPTL4). These changes would be predicted to increase rather than decrease TG levels. The TG reduction by fenofibrate was maintained in Apoa5-deficient mice, further indicating that APOA5 is not involved in TG lowering by fenofibrate. In humans, fenofibrate reduced TG without increasing APOA5 levels or reducing ANGPTL3/8 levels. In addition, fenofibrate treatment increased levels of ANGPTL3, ANGPTL4/8, and CD-ANGPTL4. The collective human and mouse data suggest that APOA5 and ANGPTL3/4/8 proteins do not mediate fenofibrate-induced TG lowering. Our findings are noteworthy because elevated levels of ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 are associated with increased cardiovascular mortality.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101050"},"PeriodicalIF":4.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773812","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}

引用次数: 0

Navigating the Lipid Universe with LipidLibrarian: A Cross-Linked Database for Lipidomics Data Integration. 用LipidLibrarian导航脂质宇宙：脂质组学数据集成的交叉链接数据库。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-27 DOI: 10.1016/j.jlr.2026.101049

Felix Niedermaier, Konstantinos Mechteridis, Konstantin Pelz, Vivian Würf, Nikolai Köhler, Josch K Pauling

{"title":"Navigating the Lipid Universe with LipidLibrarian: A Cross-Linked Database for Lipidomics Data Integration.","authors":"Felix Niedermaier, Konstantinos Mechteridis, Konstantin Pelz, Vivian Würf, Nikolai Köhler, Josch K Pauling","doi":"10.1016/j.jlr.2026.101049","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101049","url":null,"abstract":"There are numerous public resources and guidelines available for lipidomics research, including standard nomenclatures, classification systems, and lipid databases. However, these resources are not always aligned with one another, making it difficult to find and compare information on the same lipid across different databases. To tackle these challenges we present LipidLibrarian, a lipid search engine that enables a combined search of all major lipid databases by aggregating the available information and presenting it in a unified manner. The three main sources of information that build the foundation of LipidLibrarian as a comprehensive search-engine are SwissLipids, LIPID MAPS and ALEX123. Furthermore, various secondary resources such as LION/web, LINEX, LipidLynxX, and Goslin were incorporated to enhance the results and conduct name and hierarchy conversions. LipidLibrarian is accessible via a user-friendly website, allowing the user to query lipids using their trivial names, shorthand notations, database identifiers, or their masses. Alternatively, LipidLibrarian can be accessed as a Python package for integration into high-throughput lipidomics pipelines. The output of a LipidLibrarian query is split into multiple categories, such as nomenclature, database identifiers, masses, adducts, fragments, ontology terms, and reactions. For each of these categories, LipidLibrarian aggregates the results from all databases and provides the source from which each value originates. This enables the user to quickly assess if the databases contain differing or conflicting information. In summary, LipidLibrarian provides an effortless, comprehensive and automated search for lipid information, thereby accelerating the research workflow and making it a meaningful tool for the scientific community; lipidlibrarian.ciobio.io.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101049"},"PeriodicalIF":4.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773836","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}

引用次数: 0

Raman analysis of breast cancer-associated adipocytes: a chemometric pipeline for lipid biochemistry profiling. 乳腺癌相关脂肪细胞的拉曼分析：脂质生化分析的化学计量管道。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-20 DOI: 10.1016/j.jlr.2026.101046

Pooja Girish, Pascaline Bouzy, Emilie Buache, Catherine Muller, Charlotte Vaysse, Landry Blanc, Sebastien Legendre, Olivier Piot

{"title":"Raman analysis of breast cancer-associated adipocytes: a chemometric pipeline for lipid biochemistry profiling.","authors":"Pooja Girish, Pascaline Bouzy, Emilie Buache, Catherine Muller, Charlotte Vaysse, Landry Blanc, Sebastien Legendre, Olivier Piot","doi":"10.1016/j.jlr.2026.101046","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101046","url":null,"abstract":"This study describes an integrated chemometric pipeline to analyse Raman spectra from breast tissue adipocytes, distinguishing Cancer associated adipocytes (CAAs) from normal adipocytes (NAs) and assessing the impact of obesity. Raman spectra were acquired from NAs and CAAs from the invasive front of breast tumor in 10 patients (5 normal weight, NW; 5 obese weight, OW). Extended Multiplicative Scatter Correction (EMSC) was adapted to correct carotenoid spectral interference. Random forest (RF) classifier was used for identifying discriminant wavenumbers and Uniform Manifold Approximation and Projection (UMAP) for visualization, with clustering quality assessed using silhouette scores. The results show the effectiveness of the pipeline in correcting the interferences and in identifying the key discriminant spectral regions. Informative wavenumbers highlighted differences in lipid unsaturation (C=C stretch at 1655 cm-1, =C-H stretching at 3010 cm-1 ), triglyceride composition (C=O stretching at 1745 cm-1) and chain packing (CH2 stretching 2840-2880 cm-1), revealing greater biochemical heterogeneity in CAAs. In summary, this integrative approach of data processing and analysing provides an effective framework for studying subtle spectral differences in samples. The pipeline successfully distinguished CAA and NA phenotypes, establishing a foundation for identifying spectroscopic biomarkers of adipocyte pathological remodelling in breast cancer.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101046"},"PeriodicalIF":4.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773862","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}

引用次数: 0

Causal Statistical Association between Remnant Cholesterol and Coronary Heart Disease: Genetic Insights into the PSRC1-CELSR2-SORT1 Gene Cluster. 残余胆固醇与冠心病之间的因果统计关联：PSRC1-CELSR2-SORT1基因簇的遗传见解

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-20 DOI: 10.1016/j.jlr.2026.101047

Guiyuan Han, Chon Lok Lei, Yu Shi, Jiajia Gao, Xiaoying Liu, Ke Peng, Yunpeng Cai, Pui Man Hoi, Yichong Li

{"title":"Causal Statistical Association between Remnant Cholesterol and Coronary Heart Disease: Genetic Insights into the PSRC1-CELSR2-SORT1 Gene Cluster.","authors":"Guiyuan Han, Chon Lok Lei, Yu Shi, Jiajia Gao, Xiaoying Liu, Ke Peng, Yunpeng Cai, Pui Man Hoi, Yichong Li","doi":"10.1016/j.jlr.2026.101047","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101047","url":null,"abstract":"Background: Remnant cholesterol (RC) is increasingly recognized as an independent contributor to coronary heart disease (CHD) risk beyond low-density lipoprotein cholesterol (LDL-C). However, its causal roles, genetic determinants, tissue-specific regulation, and relevance across ancestrally diverse populations remain incompletely characterized.Methods: Associations between RC and incident CHD were evaluated in the UK Biobank employing Cox regression and restricted cubic splines models, including subgroup analyses by LDL-C levels. Causality was assessed using two-sample Mendelian randomization (MR) and colocalization using genome-wide summary statistics from UK Biobank and FinnGen. Findings were validated in a multi-ancestry dataset. Genetic regulatory mechanisms were explored using tissue-specific MR integrating expression quantitative trait locus. Lipid-wide MR was used to evaluate gene effects across multiple lipid traits. Comparison between identified genes and established lipid-modifying target genes was conducted.Results: RC showed a size-specific, LDL-C-independent association with CHD, which remained strong among individuals with normal LDL-C (<2.6 mmol/L). Multivariable MR confirmed a robust causal relationship. Colocalization identified shared signals at the PSRC1-CELSR2-SORT1 locus, with lead variants rs12740347 and rs646776. This cluster exhibited liver-specific inverse associations with CHD, pleiotropic effects on lipid traits, and stronger influence on RC than well-known targets such as HMGCR and PCSK9.Conclusions: RC represents a potentially modifiable marker of CHD risk, especially in individuals with normal LDL-C. Hepatic expression of PSRC1-CELSR2-SORT1 protects against CHD via RC reduction, independent of LDL-C, supporting RC as promising target for CHD prevention.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101047"},"PeriodicalIF":4.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773806","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}

引用次数: 0

Alveolar type 2 cell LRP1 is needed for surfactant phospholipid metabolism and pulmonary function in mice. 肺泡2型细胞LRP1是小鼠表面活性剂磷脂代谢和肺功能所必需的。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2026-04-16 DOI: 10.1016/j.jlr.2026.101042

Rafael Ward, Soumya S Krishnan, Irina Stavrovskaya, Dativo Sanchez-Gonzalez, Christina W Agudelo, Sangmi S Park, Michelle Mai, Huchong Cai, Jennifer Martinez, Kimone Cox, Amrin Rahman, Christopher Kiang, Mattin Campos-Azpiroz, Patrick Geraghty, Elena Lopez-Rodriguez, Estela Area-Gomez, Igor Shmarakov, Ira J Goldberg, Robert F Foronjy, Itsaso Garcia-Arcos

{"title":"Alveolar type 2 cell LRP1 is needed for surfactant phospholipid metabolism and pulmonary function in mice.","authors":"Rafael Ward, Soumya S Krishnan, Irina Stavrovskaya, Dativo Sanchez-Gonzalez, Christina W Agudelo, Sangmi S Park, Michelle Mai, Huchong Cai, Jennifer Martinez, Kimone Cox, Amrin Rahman, Christopher Kiang, Mattin Campos-Azpiroz, Patrick Geraghty, Elena Lopez-Rodriguez, Estela Area-Gomez, Igor Shmarakov, Ira J Goldberg, Robert F Foronjy, Itsaso Garcia-Arcos","doi":"10.1016/j.jlr.2026.101042","DOIUrl":"https://doi.org/10.1016/j.jlr.2026.101042","url":null,"abstract":"The low-density lipoprotein receptor related protein 1 (LRP1) performs multiple functions with cell-specific regulation. Genetic variants in LRP1 are associated with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are unknown. Alveolar type 2 cells (T2C) synthesize pulmonary surfactant lipids and are involved in the pathophysiology of COPD. To investigate LRP1 in T2C, we stably transfected a human T2C cell line with LRP1-shRNA (LRP1 knockdown, LRP1 KD), and generated tamoxifen-inducible T2C-specific LRP1 knockout mice (SPC-LRP1-/-). LRP1 KD cells showed decreased surfactant phospholipid secretion and increased neutral lipid accumulation, despite lower expression of lipid metabolic genes. T2C and alveolar surfactant isolated from SPC-LRP1-/- mice showed lower concentrations of phosphatidylcholine than those from Lrp1-floxed controls. At baseline, SPC-LRP1-/- mice had decreased lung compliance and forced vital capacity. After a cigarette smoke exposure challenge, SPC-LRP1-/- mice developed worse fibrotic remodeling than control mice. Both LRP1 KD cells and T2C isolated from SPC-LRP1-/- mice exhibited increased gene expression of detoxification and inflammatory pathways associated with COPD. Finally, query of public human data showed that T2C from patients with COPD have lower expression of LRP1 and lipid metabolic genes. These data show that LRP1 is needed in T2C for surfactant lipid metabolism and pulmonary function, and suggest that reductions of LRP1 expression promote smoke-associated fibrosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"101042"},"PeriodicalIF":4.1,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716937","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}

引用次数: 0