Journal of Lipid Research最新文献

{"title":"An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant.","authors":"Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield","doi":"10.1016/j.jlr.2025.100840","DOIUrl":"10.1016/j.jlr.2025.100840","url":null,"abstract":"<p><p>Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalog of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 nonbenign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis-associated ABCB11 E297G variant. Bsep^E297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological ileal bile acid transporter inhibition improved the cholestatic phenotype of Bsep^E297G mice through increased fecal bile acid excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100840"},"PeriodicalIF":5.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293872","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}

{"title":"Liver-specific Nr1h4 deletion in mice with human-like bile acid composition causes severe liver injury.","authors":"Yusuke Mishima, Kota Tsuruya, Kinuyo Ida, Satsuki Ieda, Yutaka Inagaki, Akira Honda, Tatehiro Kagawa, Akihide Kamiya","doi":"10.1016/j.jlr.2025.100839","DOIUrl":"10.1016/j.jlr.2025.100839","url":null,"abstract":"<p><p>The farnesoid X receptor, encoded by NR1H4, is crucial for bile acid, lipid, and glucose metabolism. NR1H4 mutations in humans cause a severe liver injury called progressive familial intrahepatic cholestasis 5. However, Nr1h4 deletion in mice did not cause severe liver damage at a young age, likely because of the higher levels of hydrophilic bile acids synthesized by the mouse-specific bile acid metabolic enzymes Cyp2a12 and Cyp2c70. We aimed to assess hepatic NR1H4 function by taking advantage of the recently established Cyp2a12/Cyp2c70 double-knockout (CYPDKO) mouse model, which has a human-like bile acid composition containing mainly hydrophobic bile acids. Liver-specific Nr1h4-deficient CYPDKO mice were established using an adeno-associated virus-derived genome-editing method. Nr1h4-deficient wild-type (WT) mice showed no significant changes in marker levels for serum liver injury. In contrast, Nr1h4-deficient CYPDKO mice showed an increase in the liver/body weight ratio and serum liver injury markers, suggesting that the combination of human-like bile acid composition and Nr1h4 deletion induces liver injury. Nr1h4 deletion increased total bile acid levels in the liver through the upregulation of bile acid metabolic genes and downregulation of bile acid transporters. Conversely, overexpression of a small heterodimer partner (Shp), a downstream gene of Nr1h4, suppresses liver injury induced by Nr1h4 deletion in CYPDKO mice. Overall, liver-specific Nr1h4 deficiency induced significant liver damage in mice with human-like bile acids, unlike in WT mice, validating its use as a new animal model for cholestatic liver disease. Therefore, Shp may be a potential target for the treatment of cholestasis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100839"},"PeriodicalIF":5.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275129","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":"Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates.","authors":"Jordan W Strober, Stephan Siebel, Susan F Murray, Manuel González Rodríguez, Carlos Rodriguez-Navas Gonzalez, Daniel F Vatner","doi":"10.1016/j.jlr.2025.100838","DOIUrl":"10.1016/j.jlr.2025.100838","url":null,"abstract":"<p><p>Increased de novo lipogenesis (DNL) contributes to hyperlipidemia, MASLD, and ASCVD in insulin-resistant subjects. However, multiple pathways support lipogenesis and few have sought to quantify the contributions of the discrete metabolic pathways that contribute to lipogenesis. In this study, antisense oligonucleotides (ASOs) targeting glucokinase (Gck), lactate dehydrogenase A (Ldha), and glutamic-pyruvic transaminase 2 (Gpt2) were utilized to restrict substrate flux from lipogenic precursors in C57BL6/J mice, comparing controls (CO) and chronic overnutrition (ON). In CO mice, ASO treatments did not significantly alter lipogenesis; however, there was a trend toward decreased hepatic triglyceride content and DNL, especially with the GPT2 ASO (TG = -46.8%; DNL = -53.7%). Expectedly, increased hepatic TG content and DNL (ON vs. CO: TG = +187.9%; DNL = +41.8%) were observed in mice with chronic overnutrition. Gas chromatography-mass spectrometry analyses demonstrated increased hepatic TCA cycle metabolites (ON vs. CO: fumarate +74.2%; malate +54.0%; and citrate +43.2) and decreased hepatic concentrations of multiple amino acids (ON vs. CO: Leu -41.7%; Ile -45.0%; Val -56.3%; Ser -22.6%). With ON, TG content and DNL were reduced by restricting lipogenic carbon entry from alanine (GPT2: TG = -45.5%; DNL = -48.1%), lactate (LDHA: TG = -25.8%; DNL = -33.1%), or glucose (GCK: TG = -59.2%; DNL = -69.2%). Amino acids appear to be a consistent carbon source for DNL in mice; however, carbon entry from all sources is required to maintain the significantly elevated rates of hepatic DNL in chronically overfed mice. These findings may inform the development of novel therapies and underscore the importance of peripheral substrate storage and oxidation in the prevention of dyslipidemia in the metabolic syndrome.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100838"},"PeriodicalIF":5.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12268660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275128","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}

{"title":"Helminth-induced prostaglandin signaling and dietary shifts in PUFA metabolism promote colitis-associated cancer.","authors":"Katherine A Smith, Ella K Reed, Irina Guschina, Victoria J Tyrrell, Claire Butters, Matthew G Darby, Brunette Katsandegwaza, Alisha Chetty, William G C Horsnell, Valerie B O'Donnell, Awen Gallimore","doi":"10.1016/j.jlr.2025.100837","DOIUrl":"10.1016/j.jlr.2025.100837","url":null,"abstract":"<p><p>Oxylipins derived from dietary polyunsaturated fatty acids (PUFAs) are key determinants of intestinal health, homeostasis, and inflammatory disorders, such as colitis-associated colorectal cancer. Previous research has independently linked a high dietary omega (ω)-6:ω-3 PUFA ratio, or intestinal helminth infection, to an increased risk of colitis-associated colorectal cancer. However, whether these two factors interact to exacerbate disease risk and whether oxylipins contribute to this is unknown. In this study, we report that infection with the helminth Heligmosomoides polygyrus bakeri (Hpb) exacerbates tumor formation when combined with a high ω-6:ω-3 PUFA ratio diet. Dietary increases in tumor burden correlated with heightened levels of arachidonic acid (AA) and AA-derived lipoxygenase (LOX) oxylipins in the colon, including the 12/15-LOX product 12-hydroxyeicosatetraenoic acid, prior to disease onset. Although helminth infection further increased the production of 12/15-LOX oxylipins and increased expression of Alox15, responsible for producing these metabolites, inhibition of cyclooxygenase-dependent prostaglandin production with aspirin prevented helminth-exacerbation of disease. Helminth-infected mice exhibited increased phosphorylation of β-catenin in the colon, which was inhibited by EP2 and 4 antagonists. Moreover, administration of an EP agonist increased tumor burden in naive mice fed a high ω-6:ω-3 PUFA ratio diet, to the levels seen in helminth-exacerbation of disease. These data suggest that dietary changes in fatty acid composition coordinate with helminth-induced activation of EP signaling to exacerbate tumor development.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100837"},"PeriodicalIF":5.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258167","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}

{"title":"Targeting to high density lipoprotein cholesterol: new insights for inflammatory bowel disease treatment.","authors":"Xiaotong Wang, Xuefei Li, Kezhen Liu, Ke Yi, Yang Yang, Dongwen Wu, Xiaowei Liu","doi":"10.1016/j.jlr.2025.100836","DOIUrl":"10.1016/j.jlr.2025.100836","url":null,"abstract":"<p><p>The anti-inflammatory and vasoprotective properties of HDL-C make it best known in cardiovascular disease and sepsis. We aimed to investigate whether interventions that target HDL-C metabolism may be used for the prevention and treatment of inflammatory bowel disease (IBD). The relationship between serum lipids and IBD clinical manifestations were analyzed in both respective and prospective cohort. Later, therapeutic effect and mechanism of cholesteryl ester transfer protein inhibitors (CETPis) in IBD treatment were explored by in vivo experiments. IBD patients had significantly reduced HDL-C, which was negatively correlated with their inflammatory status. Furthermore, HDL-C level was elevated by biologics agents and HDL-C concentration pretreatment was predictive for IBD patients' future disease severity. Elevating HDL-C by CETPi before or even after the onset of experimental colitis reduced disease severity, which is associated with an ATF3-dependent anti-inflammatory reprogramming of macrophages and with enhanced gut barrier function. Together, these results demonstrate an important role of HDL-C in IBD and indicate the potential pharmacological effects of CETPi for future IBD therapy through elevation of HDL-C.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100836"},"PeriodicalIF":5.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248198","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}

{"title":"Glucosylated cholesterol accumulates in atherosclerotic lesions and impacts macrophage immune response.","authors":"André R A Marques, Inês S Ferreira, Quélia Ribeiro, Maria J Ferraz, Elizeth Lopes, Daniela Pinto, Michael Hall, José Ramalho, Marta Artola, Manuel S Almeida, Gustavo Rodrigues, Pedro Araújo Gonçalves, Jorge Ferreira, Cláudia Borbinha, João Pedro Marto, Miguel Viana-Baptista, Ryan Gouveia E Melo, Luís Mendes Pedro, Maria I L Soares, Winchil L C Vaz, Otília V Vieira, Johannes M F G Aerts","doi":"10.1016/j.jlr.2025.100825","DOIUrl":"10.1016/j.jlr.2025.100825","url":null,"abstract":"<p><p>Atherosclerosis can be described as a local acquired lysosomal storage disorder (LSD), resulting from the build-up of undegraded material in lysosomes. Atherosclerotic foam cells accumulate cholesterol (Chol) and glycosphingolipids (GSLs) within lysosomes. This constitutes the ideal milieu for the formation of a side product of lysosomal storage: glucosylated cholesterol (GlcChol), previously found in several LSDs. Using LC-MS/MS, we demonstrated that GlcChol is abundant in atherosclerotic lesions. Patients suffering from cardiovascular diseases presented unaltered plasma GlcChol levels but slightly elevated GlcChol/Chol ratios. Furthermore, we mimicked GlcChol formation in vitro by exposing macrophages (Mφ) to a pro-atherogenic oxidized cholesteryl ester, an atherosclerosis foam cell model. Additionally, Mφ exposed to GlcChol exhibited an enlarged and multinucleated phenotype. These Mφ present signs of decreased proliferation and reduced pro-inflammatory capacity. Mechanistically, the process seems to be associated with activating the AMPK signaling pathway and the cyclin-dependent kinase inhibitor 1 (CDKN1A/p21), in response to DNA damage inflicted by reactive oxygen species (ROS). At the organelle level, exposure to GlcChol impacted the lysosomal compartment, resulting in the activation of the mTOR signaling pathway and lysosomal biogenesis mediated by the transcription factor EB (TFEB). This suggests that high concentrations of GlcChol impact cellular homeostasis. In contrast, under this threshold, GlcChol formation most likely represents a relatively innocuous compensatory mechanism to cope with Chol and GSL build-up within lesions. Our findings demonstrate that glycosidase-mediated lipid modifications may play a role in the etiology of genetic and acquired LSDs, warranting further investigation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100825"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094060","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}

{"title":"Conjugated bile acids are elevated in severe calcific aortic valve stenosis.","authors":"Hannah Zhang, Negar Atefi, Arun Surendran, Jun Han, David R Goodlett, Davinder S Jassal, Ashish Shah, Amir Ravandi","doi":"10.1016/j.jlr.2025.100830","DOIUrl":"10.1016/j.jlr.2025.100830","url":null,"abstract":"<p><p>Calcific aortic valve (AV) stenosis (CAVS) is a disease associated with significant morbidity and mortality in the aging population. Recently, bile acids have been shown to play a significant role in many disease processes, and untargeted metabolomic analyses of CAVS patient valves have shown a disrupted bile acid pathway. We aimed to understand the changes in human valvular bile acids in relation to CAVS severity. A total of 100 human AVs were collected from patients undergoing AV replacement surgery. Bile acids were quantified by ultrahigh performance liquid chromatography coupled to MS/MS. Patients with mild aortic stenosis (AS) showed a distinct valvular bile acid composition compared with moderate and severe AS groups, with five bile acids being significantly elevated in patients with moderate and severe AS. These included norcholic, nordeoxycholic, glycodeoxycholic, glycocholic, and taurodeoxycholic acid. When classified by calcification score, five species were significantly different between mild and severe AS groups; four bile acids were similar when stratified based on AS severity. Using K-means clustering, we were able to distinguish valve severity by their bile acid composition. Grouping bile acids by conjugation and by primary versus secondary revealed that conjugated primary and secondary bile acids were significantly increased in stenotic valves compared with the mild AS group. Conjugated bile acids are significantly elevated in the valvular tissue of patients with severe calcific AS. These findings suggest a potential link between liver and gut microbiome physiology and bile acid pathways in contributing to the pathophysiology of valvular stenosis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100830"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131924","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}

{"title":"LDL regulates intestinal stem cell homeostasis via PPAR pathway.","authors":"Ruicheng Shi, Wei Lu, Zhiming Zhao, Bo Wang","doi":"10.1016/j.jlr.2025.100826","DOIUrl":"10.1016/j.jlr.2025.100826","url":null,"abstract":"<p><p>Epidemiological studies have highlighted a strong association between hyperlipidemia and an increased risk of cancer in the gut. Intestinal stem cells (ISCs) have been demonstrated as the cells of origin for tumorigenesis in the gut. However, the impact of hyperlipidemia on ISC homeostasis remains unclear. Here, we show that hyperlipidemia induced by LDL receptor (Ldlr) deficiency enhances ISC proliferation in vivo. Additionally, LDL treatment impairs organoid survival but increases ISC stemness ex vivo, as evidenced by the formation of poorly differentiated spheroid and higher ISC self-renewal capacity. Mechanistically, LDL treatment activates PPAR pathways, and pharmacological inhibition of PPAR and its downstream targets, including CPT1A and PDK4, mitigates the effect of LDL on ISCs. These findings demonstrate that hyperlipidemia modulates ISC homeostasis, providing new insights into the mechanism linking hyperlipidemia with tumorigenesis in the gut.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100826"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086133","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}

{"title":"The bioactive sphingolipid playbook. A primer for the uninitiated as well as sphingolipidologists.","authors":"Yusuf A Hannun, Alfred H Merrill, Chiara Luberto","doi":"10.1016/j.jlr.2025.100813","DOIUrl":"10.1016/j.jlr.2025.100813","url":null,"abstract":"<p><p>Sphingolipids and glycosphingolipids are among the most structurally diverse and complex compounds in the mammalian metabolome. They are well known to play important roles in biological architecture, cell-cell communication, and cellular regulation, and for many biological processes, multiple sphingolipids are involved. Thus, it is not surprising that untargeted genetic/transcriptomic/pharmacologic/metabolomic screens have uncovered changes in sphingolipids and sphingolipid genes/proteins while studying physiological and pathological processes. Consequently, with increasing frequency, both targeted and untargeted mass spectrometry methodologies are being used to conduct sphingolipidomic analyses. Interpretation of such large data sets and design of follow-up experiments can be daunting for investigators with limited expertise with sphingolipids (and sometimes even for someone well-versed in sphingolipidology). Therefore, this review gives an overview of essential elements of sphingolipid structure and analysis, metabolism, functions, and roles in disease and discusses some of the items to consider when interpreting lipidomics data and designing follow-up investigations.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100813"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997515","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}

{"title":"Lipoprotein (a) integrates monocyte-mediated thrombosis and inflammation in atherosclerotic cardiovascular disease.","authors":"Robert S Rosenson, Ashley M Tate, Olga G Grushko, Dilna Damodaran, Qinzhong Chen, Michael Boffa, Marlys Koschinsky, Jagat Narula, Sascha N Goonewardena","doi":"10.1016/j.jlr.2025.100820","DOIUrl":"10.1016/j.jlr.2025.100820","url":null,"abstract":"<p><p>Elevated levels of lipoprotein (a) [Lp(a)], an apolipoprotein B particle, are causally linked to atherosclerotic cardiovascular disease (ASCVD). Lp(a) is thought to promote ASCVD through multiple mechanisms, including its effects on cholesterol transport, inflammation, and thrombosis. This study defines the mechanisms that integrate Lp(a)-mediated cholesterol accumulation, inflammation, and thrombosis. In this study, we employed systems biology approaches, including proteomics, transcriptomics, and mass cytometry, to define the immune cellular and molecular phenotypes in patients with ASCVD having high and low Lp(a) levels and the molecular mechanisms through which Lp(a) mediates monocyte-driven inflammation and thrombosis. In 64 stable patients with ASCVD (41 with high Lp(a) [median Lp(a) 228.7 nmol/L] and 23 with low Lp(a) [median Lp(a) 17.8 nmol/L]), we found that circulating markers of inflammation (CCL28, IL-17D) and vascular dysfunction (tissue factor [TF]; 6.4 vs. 5.7 normalized protein expression (NPX); P = 0.01) were elevated in patients with high Lp(a) levels compared with those with low Lp(a) levels. Although total monocyte and hsCRP levels were similar between the groups, CD14+ monocytes from patients with ASCVD having an elevated Lp(a) were primed and expressed more TF at baseline and in response to stress. Mechanistically, we found that Lp(a) itself can activate monocytes through Toll-like receptor 2 (TLR2) and nuclear factor kappa B (NFκB) signaling, driving both the induction of TF and TF activity. Overall, these studies are the first to link Lp(a) to monocyte-mediated inflammation and thrombosis. This study demonstrates a novel mechanism through TLR2, NFκB, and monocyte TF by which Lp(a) amplifies immunothrombotic risk.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100820"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010605","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}