Journal of Lipid Research最新文献

{"title":"The steady-state level of plasma membrane ceramide is regulated by neutral sphingomyelinase 2.","authors":"Anne G Ostermeyer-Fay, Abhay Kanodia, Ranjana Pathak, Maria Jose Hernandez-Corbacho, Aarnoud C van der Spoel, Yusuf A Hannun, Daniel Canals","doi":"10.1016/j.jlr.2024.100719","DOIUrl":"10.1016/j.jlr.2024.100719","url":null,"abstract":"<p><p>During the last 30 years, an increasing number of cellular functions have been reported to be regulated by the lipid ceramide. The diversity in the ceramide structure, leading to tens of ceramide species and the discrete distribution based on subcellular topology, could explain the wide variety of functions attributed to this bioactive lipid. One of these pools of ceramide resides in the plasma membrane, and several works have suggested that an increase in plasma membrane ceramide (PMCer) in response to stimulation leads to cell death and modulates cell adhesion and migration. However, there is a limitation in studying PMCer content in this location primarily due to the inability to quantify its mass. Our group recently developed a method to specifically quantitate PMCer. In this work, we interrogate what sphingolipid metabolizing enzymes are responsible for modulating the basal levels of plasma membrane ceramide. An in-silico prediction and experimental confirmation found an almost perfect correlation between the endogenous expression levels of neutral sphingomyelinase (nSMase2) and the amount of plasma membrane ceramide in unstimulated cells. Manipulating the expression levels of nSMase2, but not other candidate enzymes of ceramide metabolism, profoundly affected PMCer. Moreover, a physiologic induction of nSMase2 during cell confluence resulted in a nSMase2-dependent dramatic increase in PMCer. Together, these results identify nSMase2 as the primary enzyme to regulate plasma membrane ceramide.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100719"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780332","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":"Development and application of an LC-MS/MS method for the combined quantification of oxysterols and bile acids.","authors":"Martin Roumain, Giulio G Muccioli","doi":"10.1016/j.jlr.2024.100697","DOIUrl":"10.1016/j.jlr.2024.100697","url":null,"abstract":"<p><p>Oxysterols and bile acids are interconnected bioactive lipids playing pivotal roles in diverse physiological and pathological processes. For this reason, they are increasingly studied together for their implications in various diseases. However, due to analytical challenges inherent to the nature of these analytes, very few methods have been developed for the simultaneous analysis of these lipids. We here report the development of a sensitive LC-MS/MS method for the combined quantification of 18 oxysterols, 11 unconjugated, 15 conjugated bile acids, and 1 bile acid precursor, using 8 isotope-labeled internal standards, addressing the need for a more comprehensive analysis of these interesting lipid families. During the method development, we investigated different extraction protocols, set up a purification step, and achieved chromatographic separation for these lipids, overcoming challenges such as the large number of analytes, isomers, and wide range of polarity across the analytes. Finally, the method was successfully applied to the analysis of preclinical and clinical samples, quantifying 12 oxysterols and 14 bile acids in human plasma, 10 oxysterols and 18 bile acids in mouse plasma from the vena cava, and 10 oxysterols and 20 bile acids in mouse plasma from the portal vein within a single chromatographic run.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100697"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667849","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 bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice.","authors":"Vera F Monteiro-Cardoso, Xin Yi Yeo, Han-Gyu Bae, David Castano Mayan, Mariam Wehbe, Sejin Lee, Kumar Krishna-K, Seung Hyun Baek, Leon F Palomera, Lik Hang Wu, Leroy S Pakkiri, Sangeetha Shanmugam, Kai Ping Sem, Mun Geok Yew, Matthew P Parsons, Michael R Hayden, Leonard L L Yeo, Vijay K Sharma, Chester Drum, Elisa A Liehn, Sreedharan Sajikumar, Svend Davanger, Dong-Gyu Jo, Mark Y Y Chan, Benjamin Y Q Tan, Sangyong Jung, Roshni R Singaraja","doi":"10.1016/j.jlr.2024.100712","DOIUrl":"10.1016/j.jlr.2024.100712","url":null,"abstract":"<p><p>Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1^-/-, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1^-/- and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1^-/- brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1^-/- mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100712"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693141","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":"Porcine transient receptor potential channel 1 promotes adipogenesis and lipid deposition.","authors":"Yu Fu, Xin Hao, Jingru Nie, Peng Shang, Xinxing Dong, Bo Zhang, Dawei Yan, Hao Zhang","doi":"10.1016/j.jlr.2024.100718","DOIUrl":"10.1016/j.jlr.2024.100718","url":null,"abstract":"<p><p>Adipose tissue, an important organ involved in energy metabolism and endocrine, is closely related to animal meat quality and human health. Transient receptor potential channel 1 (TRPC1), an ion transporter, is adipocytes' major Ca²⁺ entry channel. However, its function in fat deposition is poorly understood, particularly in pigs, which are both an ideal model for human obesity research and a primary meat source for human diets. In the present investigation, our findings demonstrate a prominent expression of TRPC1 within the adipose tissue of pigs with a strong fat deposition ability. Functional analysis showed that TRPC1 promotes primary preadipocyte proliferation and adipogenic differentiation. In vivo, transgenic mice expressing porcine TRPC1 exhibited aggravated high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, TRPC1 may facilitate adipogenesis via activating phosphatidylinositol 3 kinase/AKT and β-catenin signaling pathways. Our research underscores the pivotal role of porcine TRPC1 as a positive regulator in adipogenesis and lipid accumulation processes, providing a potential target for improving animal meat quality and treating obesity-related diseases in humans.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100718"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780314","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":"CD14^loCD301b⁺ macrophages gathering as a proangiogenic marker in adipose tissues.","authors":"Yibing Lv, Yidan Zheng, Shanshan Su, Junyi Xiao, Jie Yang, Lingyun Xiong, Yanyan Guo, Xiaoqi Zhou, Nengqiang Guo, Ping Lei","doi":"10.1016/j.jlr.2024.100720","DOIUrl":"10.1016/j.jlr.2024.100720","url":null,"abstract":"<p><p>The role of the monocyte marker CD14 in the regulation of obesity is increasingly recognized. Our observations indicated that Cd14^-/- mice exhibited a leaner body shape compared to their wild-type (WT) counterparts. And the loss of CD14 alleviated high-fat diet-induced obesity in mice. In human subjects, CD14 level was tested to be positively correlated with overweight and obesity. However, the relationship between CD14 and the development of obesity remains only partially understood. To investigate the underlying mechanisms, adipose tissues (ATs) from Cd14^-/- and WT mice were subjected to deep RNA sequencing. Gene Ontology enrichment analysis revealed a significant enhancement of angiogenesis-related function in the Cd14^-/- epididymal adipose tissues compared to WT counterpart, which was accompanied by an upregulation of Cd301b. Subsequent assays confirmed the enhanced angiogenesis and more accumulation of CD301b⁺ macrophages in Cd14^-/- epididymal adipose tissues. Because Igf1 expression has been suggested to be associated with Cd301b expression through pseudotime analysis, we found it was insulin-like growth factor 1 secreted from Cd14^-/- macrophages that mediated the angiogenesis enhancement. Collectively, our findings indicate that CD14 deficiency increased the accumulation of CD14^loCD301b⁺ macrophages in ATs, which may serve as a proangiogenic marker, providing novel insights into the relationship between CD14 and obesity development.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100720"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791565","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":"Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.","authors":"Shelley Barnhart, Masami Shimizu-Albergine, Eyal Kedar, Vishal Kothari, Baohai Shao, Melissa Krueger, Cheng-Chieh Hsu, Jingjing Tang, Jenny E Kanter, Farah Kramer, Danijel Djukovic, Vadim Pascua, Yueh-Ming Loo, Lucrezia Colonna, Sadie J Van den Bogaerde, Jie An, Michael Gale, Karen Reue, Edward A Fisher, Sina A Gharib, Keith B Elkon, Karin E Bornfeldt","doi":"10.1016/j.jlr.2024.100730","DOIUrl":"10.1016/j.jlr.2024.100730","url":null,"abstract":"<p><p>Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100730"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828927","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":"Role of dietary and nutritional interventions in ceramide-associated diseases.","authors":"Shengnan Wang, Zihui Jin, Biyu Wu, Andrew J Morris, Pan Deng","doi":"10.1016/j.jlr.2024.100726","DOIUrl":"10.1016/j.jlr.2024.100726","url":null,"abstract":"<p><p>Ceramides are important intermediates in sphingolipid metabolism and serve as signaling molecules with independent biological significance. Elevated cellular and circulating ceramide levels are consistently associated with pathological conditions including cardiometabolic diseases, neurological diseases, autoimmune diseases, and cancers. Although pharmacological inhibition of ceramide formation often protects against these diseases in animal models, pharmacological modulation of ceramides in humans remains impractical. Dietary interventions including the Mediterranean diet, lacto-ovo-vegetarian diet, calorie-restricted diet, restriction of dairy product consumption, and dietary supplementation with polyunsaturated fatty acids, dietary fibers, and polyphenols, all have beneficial effects on modulating ceramide levels. Mechanistic insights into these interventions are discussed. This article reviews the relationships between ceramides and disease pathogenesis, with a focus on dietary intervention as a viable strategy for lowering the concentration of circulating ceramides.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100726"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818338","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":"Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D.","authors":"Lihua Wang, Siyu Wang, Jason A Anema, Vaha A Moghaddam, Yanli Lu, Shiow Lin, E Warwick Daw, Allison L Kuipers, Iva Miljkovic, Michael Brent, Gary J Patti, Bharat Thygarajan, Joseph M Zmuda, Michael A Province, Ping An","doi":"10.1016/j.jlr.2024.100702","DOIUrl":"10.1016/j.jlr.2024.100702","url":null,"abstract":"<p><p>Triglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n = 1,384). Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling and adjusted for age, sex, field centers, and principal components. GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based identity-by-descent estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (P = 1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds exceeding 3 on 3q28 (logarithm of the odds = 4.1). Using a subset of 25 linkage-enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2 [eukaryotic translation initiation factor 4A2]/ADIPOQ-rs114108468, p = 5e-6, minor allele frequency = 1.8%; TPRG1-rs16864075, p = 3e-6, minor allele frequency = 8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p = 7e-5)/ADIPOQ (P = 3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (P = 0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort observed modest effect of these loci on ΔTHR. Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100702"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667857","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 sterol panel for rare lipid disorders: sitosterolemia, cerebrotendinous xanthomatosis and Smith-Lemli-Opitz syndrome.","authors":"Alexander Bauer Westbye, Lili L Dizdarevic, Sandra R Dahl, Emil Andreas Asprusten, Yngve Thomas Bliksrud, Anita Lövgren Sandblom, Ulf Diczfalusy, Per M Thorsby, Kjetil Retterstøl","doi":"10.1016/j.jlr.2024.100698","DOIUrl":"10.1016/j.jlr.2024.100698","url":null,"abstract":"<p><p>Disease-specific sterols accumulate in the blood of patients with several rare lipid disorders. Biochemical measurement of these sterols is important for correct diagnosis and sometimes monitoring of treatment. Existing methods to measure sterols in blood, particularly plant sterols, are often laborious and time consuming. Partly as a result, clinical access to sterol measurements is limited in many parts of the world. A simple and rapid method to extract free sterols from human serum and quantitate their concentration using isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization was developed. The method was designed to be compatible with routine workflows (e.g., 96-well format) in a clinical lab and extensively validated. Serum from at least 125 controls were analyzed and used to estimate the upper reference limits for sitosterol, campesterol, stigmasterol, desmosterol, 7-dehydrocholesterol (7DHC), lathosterol, and cholestanol. Serum from patients with the rare lipid disorders sitosterolemia (n = 7), Smith-Lemli-Opitz syndrome (SLOS; n = 1), and cerebrotendinous xanthomatosis (CTX; n = 1) were analyzed. All seven sitosterolemia patients had greatly elevated levels of free plant sterols (sitosterol, campesterol, and stigmasterol) compared to the controls. The SLOS serum contained massively increased concentrations of 7DHC. CTX serum contained greatly increased concentrations of cholestanol, as well as 7DHC and lathosterol. Spiking experiments indicated that the method is likely also useful for the diagnosis of desmosterolosis and lathosterolosis. The reported method is a relatively simple and fast LC-MS/MS method capable of quantitating diagnostically important sterols and differentiated patients with three rare lipid disorders from controls.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100698"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11714705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681823","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":"Lipid trajectories improve risk models for Alzheimer's disease and mild cognitive impairment.","authors":"Bruce A Chase, Roberta Frigerio, Chad J Yucus, Smita Patel, Demetrius Maraganore, Alan R Sanders, Jubao Duan, Katerina Markopoulou","doi":"10.1016/j.jlr.2024.100714","DOIUrl":"10.1016/j.jlr.2024.100714","url":null,"abstract":"<p><p>In this retrospective, case-control study, we tested the hypothesis that blood-lipid concentrations during the decade prior to cognitive symptom onset can inform risk prediction for Alzheimer's disease (AD) and stable mild cognitive impairment (MCI). Clinically well-characterized cases were diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria; MCI cases had been stable for ≥5 years; and controls were propensity matched to cases at symptom onset (MCI: 116 cases, 435 controls; AD: 215 cases, 483 controls). Participants were grouped based on (i) longitudinal trajectories and (ii) quintile of variability independent of the mean (VIM) for total cholesterol, HDL-C, low-density lipoprotein cholesterol, non-HDL-C, and ln(triglycerides). Risk models evaluated the contributions of lipid trajectory and VIM groups relative to APOE genotype or polygenic risk scores (PRSs) for AD and lipid levels and major lipoprotein confounders: age, lipid-lowering medications, comorbidities, and other longitudinal correlates of blood-lipid concentrations. In models with AD-PRS, higher MCI-risk was associated with the two lower HDL-C trajectories [odds ratios: 3.8(1.3-11.3; P = 0.014), 3.2(1.1-9.3; P = 0.038), relative to the high trajectory], and the lowest VIM quintile of non-HDL-C [odds ratio: 2.2 (1.3-3.8: P = 0.004), relative to quintiles 2-5]. Higher AD-risk was associated with the two lower HDL-C trajectories [odds ratios: 2.8(1.5-5.1; P = 0.001), 3.7 (2.0-7.0; P < 0.001)], and the lowest VIM quintile of total cholesterol [odds ratio: 2.5(1.5-4.0: P < 0.001)]. Inclusion of lipid-trajectory and VIM groups improved risk-model predictive performance independent of APOE and AD or lipid-level PRSs, providing important real-world perspectives on how longitudinal levels and variation of blood-lipid concentrations contribute to risk of cognitive decline.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100714"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716205","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}