Journal of Lipid Research最新文献

{"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 (Gly¹¹²⁷-Cys¹¹⁴⁰) 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":"2025-03-22","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}

{"title":"Apolipoprotein A1 deficiency increases macrophage apoptosis and necrotic core development in atherosclerotic plaques in a Bim-dependent manner.","authors":"Alexander S Qian, George E G Kluck, Pei Yu, Leticia Gonzalez, Elizabeth Balint, Bernardo L Trigatti","doi":"10.1016/j.jlr.2025.100782","DOIUrl":"10.1016/j.jlr.2025.100782","url":null,"abstract":"<p><p>In advanced atherosclerotic lesions, macrophage apoptosis contributes to plaque progression and the formation of necrotic cores, rendering plaques vulnerable to rupture. The proapoptotic protein B-cell lymphoma 2 [Bcl-2] interacting mediator of cell death (Bim) plays a crucial role in mediating apoptosis in macrophages under prolonged endoplasmic reticulum stress. HDL has been shown to suppress macrophage apoptosis induced by endoplasmic reticulum stressors. To investigate the impact of apolipoprotein A1 (ApoA1) deficiency, associated with reduced HDL levels, on necrotic core growth and plaque apoptosis, we introduced ApoA1 deficiency into low-density lipoprotein receptor (LDLR) knockout mice and fed them a high-fat diet for 10 weeks. ApoA1-deficient Ldlr KO mice developed advanced plaques characterized by large necrotic cores, increased apoptosis, and elevated Bim expression in macrophages within the plaques. To assess whether deletion of Bim could mitigate this development, mice underwent bone marrow transplantation with bone marrow from either Bim-deficient mice or from mice with a deletion of myeloid-derived Bim driven by LyzM-cre. Inhibiting Bim in all bone marrow-derived cells led to leukocytosis, reductions in plasma cholesterol and triglyceride levels, and decreased plaque apoptosis, necrotic core, and plaque sizes in ApoA1 and Ldlr double-KO mice but not in Ldlr KO mice. Likewise, conditional deletion of Bim in the myeloid compartment of ApoA1 and Ldlr double-KO mice also reduced apoptosis, necrotic core sizes, and plaque sizes, without inducing leukocytosis or lowering plasma cholesterol levels. These findings suggest that ApoA1 deficiency triggers apoptosis in myeloid cells through a Bim-dependent pathway, significantly contributing to the development of necrotic cores and the progression of atherosclerotic plaques.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100782"},"PeriodicalIF":5.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor.","authors":"Yi Xu, Saixuan Li, Yiran Xu, Xiaoqin Sun, Yuqing Wei, Yuejun Wang, Shuang Li, Yongqi Ji, Keyi Hu, Yuxia Xu, Cuiqing Zhu, Bin Lu, Dandan Wang","doi":"10.1016/j.jlr.2025.100781","DOIUrl":"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":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical lipidomics reveals high individuality and sex specificity of circulatory lipid signatures: a prospective healthy population study.","authors":"Jessica Medina, Nicolas Goss, Gonçalo Dos Santos Correia, Rebecca Borreggine, Tony Teav, Zoltan Kutalik, Pedro Marques Vidal, Hector Gallart-Ayala, Julijana Ivanisevic","doi":"10.1016/j.jlr.2025.100780","DOIUrl":"10.1016/j.jlr.2025.100780","url":null,"abstract":"<p><p>Lipid metabolism and circulatory lipid levels are tightly associated with the (cardio)metabolic health. Consequently, MS-based lipidomics has emerged as a powerful phenotyping tool in epidemiological, human population, and in clinical intervention studies. However, ensuring high-throughput and reproducible measurement of a wide panel of circulatory lipid species in large-scale studies poses a significant challenge. Here, we applied a recently developed quantitative LC-MS/MS lipidomics approach to a subset of 1,086 fasted plasma samples belonging to apparently healthy participants from prospective Lausanne population study. This high-coverage and high-throughput hydrophilic interaction liquid chromatography-based methodology allowed for the robust measurement of 782 circulatory lipid species spanning 22 lipid classes and six orders of magnitude-wide concentration range. This was achieved by combining semiautomated sample preparation using a stable isotope dilution approach and the alternate analysis of National Institute of Standards and Technology plasma reference material, as a quality control. Based on National Institute of Standards and Technology quality control analysis, median between-batch reproducibility was 8.5%, over the course of analysis of 13 independent batches comprising 1,086 samples collected from 364 individuals at three time points. Importantly, the biological variability, per lipid species, was significantly higher than the batch-to-batch analytical variability. Furthermore, the significantly lower between-subject (than within-subject) variability and unsupervised sample clustering demonstrated the high individuality and sex specificity of circulatory lipidome. The most prominent sex differences were reported for sphingomyelins and ether-linked phospholipids present in significantly higher concentrations in female plasma. The high individuality and sex specificity of circulatory lipidome constitute important pre-requisites for the application of lipidomics in next-generation metabolic health monitoring.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100780"},"PeriodicalIF":5.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

{"title":"Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity.","authors":"Weinan Zhou, Sarith R Bandara, Kyungwon Ko, Oludemilade Akinrotimi, Diego Hernández-Saavedra, Emily Richter, Noah Brauer, Taylor J Woodward, Heather B Bradshaw, Cecilia Leal, Sayeepriyadarshini Anakk","doi":"10.1016/j.jlr.2025.100754","DOIUrl":"10.1016/j.jlr.2025.100754","url":null,"abstract":"<p><p>The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high-fat diet (HFD)-fed control mice. Moreover, upon HFD challenge, these effects are worsened in adipocyte-specific Fxr knockout mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that Faah inhibition or deletion is linked to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100754"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408738","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":"Cadmium-cardiolipin disruption of respirasome assembly and redox balance through mitochondrial membrane rigidification.","authors":"Nadiya Romanova, Kevin Sule, Travis Issler, Daniel Hebrok, Marcus Persicke, Frank Thévenod, Elmar J Prenner, Wing-Kee Lee","doi":"10.1016/j.jlr.2025.100750","DOIUrl":"10.1016/j.jlr.2025.100750","url":null,"abstract":"<p><p>The environmental pollutant cadmium (Cd) poses a threat to human health through the consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface), and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40 mol % POPC, 35 mol % DOPE, 20 mol % TOCL, 5 mol % SAPI) nanoliposomes were rigidified by 25 μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III₂+IV_n SC formation after 5 μM Cd for 6 h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1 μM), yet α-tocopherol-insensitive. Moreover, MTP-131 attenuated Cd-induced H₂O₂ (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5 μM, 24 h) cytotoxicity (∼25%) by MTT assay, Cd (5 μM, 3 h)-induced ROS and mitochondrial membrane rigidification by Cd (1 μM, 1 h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100750"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066112","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":"Cholesterol affects the binding of proteins to phosphatidic acid without influencing its ionization properties.","authors":"Desmond Owusu Kwarteng, Alexander Wolf, Madisyn Langdon, Nawal Kassas, Nicolas Vitale, Edgar Eduard Kooijman","doi":"10.1016/j.jlr.2025.100749","DOIUrl":"10.1016/j.jlr.2025.100749","url":null,"abstract":"<p><p>Phosphatidic acid (PA) through its unique negatively charged phosphate headgroup binds to various proteins to modulate multiple cellular events. To perform such diverse signaling functions, the ionization and charge of PA's headgroup rely on the properties of vicinal membrane lipids and changes in cellular conditions. Cholesterol has conspicuous effects on lipid properties and membrane dynamics. In eukaryotic cells, its concentration increases along the secretory pathway, reaching its highest levels toward the plasma membrane. Moreover, membrane cholesterol levels are altered in certain diseases such as Alzheimer's disease, cancer, and in erythrocytes of hypercholesteremia patients. Hence, those changing levels of cholesterol could affect PA's charge and alter binding to effector protein. However, no study has investigated the direct impact of cholesterol on the ionization properties of PA. Here, we used ³¹P MAS NMR to explore the effects of increasing cholesterol concentrations on the chemical shifts and pKa2 of PA. We find that, while the chemical shifts of PA change significantly at high cholesterol concentrations, surprisingly, the pKa2 and charge of PA under these conditions are not modified. Furthermore, using in vitro lipid binding assays we found that higher cholesterol levels increased PA binding of the Spo20p PA sensor. Finally, in cellulo experiments demonstrated that depleting cholesterol from neurosecretory cells halts the recruitment of this sensor upon PA addition. Altogether, these data suggest that the intracellular cholesterol gradient may be an important regulator of proteins binding to PA and that disruption of those levels in certain pathologies may also affect PA binding to its target proteins and subsequent signaling pathways.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100749"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066120","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":"PI3KC2β depletion rescues endosomal trafficking defects in Mtm1 knockout skeletal muscle cells.","authors":"Mélanie Mansat, Afi Oportune Kpotor, Anne Mazars, Gaëtan Chicanne, Bernard Payrastre, Julien Viaud","doi":"10.1016/j.jlr.2025.100756","DOIUrl":"10.1016/j.jlr.2025.100756","url":null,"abstract":"<p><p>Phosphoinositides constitute a class of seven phospholipids found in cell membranes, regulating various cellular processes like trafficking and signaling. Mutations in their metabolizing enzymes are implicated in several pathologies, including X-linked myotubular myopathy, a severe myopathy caused by mutations in the MTM1 gene. MTM1 (myotubularin 1) acts as a phosphoinositide 3-phosphatase, targeting PI3P (phosphatidylinositol 3-phosphate) and phosphatidylinositol 3,5-bisphosphate, crucial for endolysosomal trafficking. Studies in X-linked myotubular myopathy animal models have demonstrated that loss of MTM1 results in PI3P accumulation in muscle. Moreover, inactivating the class II phosphoinositide 3-kinase beta rescues the pathological phenotype and decreases PI3P levels, suggesting that the normalization of PI3P levels could be responsible for that rescue mechanism. In this study, using an Mtm1-KO skeletal muscle cell line, we investigated the localization of the PI3P pool metabolized by MTM1 in endosomal compartments. Our findings reveal that MTM1 metabolizes a pool of PI3P on EEA1 (early endosome antigen 1)-positive endosomes, leading to impaired Rab4 recycling vesicle biogenesis in the absence of MTM1. Furthermore, depletion of class II phosphoinositide 3-kinase beta rescued Mtm1-KO cell phenotype, normalized PI3P level on EEA1-positive endosomes, and restored Rab4-positive vesicle biogenesis. These results indicate that MTM1 is critical for the homeostasis of endosomal trafficking, and that depletion of MTM1 potentially alters cargo recycling through Rab4-positive vesicle trafficking.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100756"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425602","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":"A multi-ancestry genome-wide association study and evaluation of polygenic scores of LDL-C levels.","authors":"Umm-Kulthum Ismail Umlai, Salman M Toor, Yasser A Al-Sarraj, Shaban Mohammed, Moza S H Al Hail, Ehsan Ullah, Khalid Kunji, Ayman El-Menyar, Mohammed Gomaa, Amin Jayyousi, Mohamad Saad, Nadeem Qureshi, Jassim M Al Suwaidi, Omar M E Albagha","doi":"10.1016/j.jlr.2025.100752","DOIUrl":"10.1016/j.jlr.2025.100752","url":null,"abstract":"<p><p>The genetic determinants of low-density lipoprotein cholesterol (LDL-C) levels in blood have been predominantly explored in European populations and remain poorly understood in Middle Eastern populations. We investigated the genetic architecture of LDL-C variation in Qatar by conducting a genome-wide association study (GWAS) on serum LDL-C levels using whole genome sequencing data of 13,701 individuals (discovery; n = 5,939, replication; n = 7,762) from the population-based Qatar Biobank (QBB) cohort. We replicated 168 previously reported loci from the largest LDL-C GWAS by the Global Lipids Genetics Consortium (GLGC), with high correlation in allele frequencies (R² = 0.77) and moderate correlation in effect sizes (Beta; R² = 0.53). We also performed a multi-ancestry meta-analysis with the GLGC study using MR-MEGA (Meta-Regression of Multi-Ethnic Genetic Association) and identified one novel LDL-C-associated locus; rs10939663 (SLC2A9; genomic control-corrected P = 1.25 × 10^-8). Lastly, we developed Qatari-specific polygenic score (PGS) panels and tested their performance against PGS derived from other ancestries. The multi-ancestry-derived PGS (PGS000888) performed best at predicting LDL-C levels, whilst the Qatari-derived PGS showed comparable performance. Overall, we report a novel gene associated with LDL-C levels, which may be explored further to decipher its potential role in the etiopathogenesis of cardiovascular diseases. Our findings also highlight the importance of population-based genetics in developing PGS for clinical utilization.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100752"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255870","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}