Journal of Lipid Research最新文献_第2页

Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-12-06 DOI: 10.1016/j.jlr.2024.100723

Craig A Swearingen, John H Sloan, Grace M Rhodes, Robert W Siegel, Nico Bivi, Yuewei Qian, Robert J Konrad, Michael Boffa, Marlys Koschinsky, John Krege, Giacomo Ruotolo, Stephen J Nicholls, Laura F Michael, Yi Wen

{"title":"Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin.","authors":"Craig A Swearingen, John H Sloan, Grace M Rhodes, Robert W Siegel, Nico Bivi, Yuewei Qian, Robert J Konrad, Michael Boffa, Marlys Koschinsky, John Krege, Giacomo Ruotolo, Stephen J Nicholls, Laura F Michael, Yi Wen","doi":"10.1016/j.jlr.2024.100723","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100723","url":null,"abstract":"Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor, and there is considerable interest in developing Lp(a)-lowering therapeutics for cardiovascular prevention. Current commercial Lp(a) assays measure total apolipoprotein(a) [apo(a)] and may be insufficient to accurately measure Lp(a) concentrations and determine Lp(a) lowering by a new class of small-molecule Lp(a) formation inhibitors such as muvalaplin. We developed a novel immunoassay that measures only Lp(a) particles. This intact Lp(a) assay demonstrated robust analytical performance, was insensitive to apo(a) isoform size, and correlated with a liquid chromatography-tandem mass spectrometry method. Muvalaplin phase I multiple ascending dose study samples and lepodisiran, a small interfering RNA that lowers Lp(a), phase I single ascending dose study samples were analyzed using the intact Lp(a) assay and commercial assays. The Lp(a)-lowering efficacy of muvalaplin was underestimated by the commercial assay measuring total apo(a) compared with the intact Lp(a) assay specifically measuring Lp(a) particles. In contrast, the Lp(a)-lowering effect of lepodisiran was clinically comparable between the intact Lp(a) assay and commercial assay. This novel intact Lp(a) assay provides a more accurate approach for the assessment of Lp(a)-lowering agents and study of Lp(a)-associated risk compared with currently available assays.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100723"},"PeriodicalIF":5.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794907","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

CD14^loCD301b⁺ macrophages gathering as a proangiogenic marker in adipose tissues.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-12-05 DOI: 10.1016/j.jlr.2024.100720

Yibing Lv, Yidan Zheng, Shanshan Su, Junyi Xiao, Jie Yang, Lingyun Xiong, Yanyan Guo, Xiaoqi Zhou, Nengqiang Guo, Ping Lei

{"title":"CD14loCD301b+ 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":"https://doi.org/10.1016/j.jlr.2024.100720","url":null,"abstract":"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 (HFD)-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 (AT) 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-/- epWAT 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-/- epWAT. Because Igf1 expression has been suggested to be associated with Cd301b expression through pseudotime analysis, we found it was IGF-1 secreted from Cd14-/- macrophages that mediated the angiogenesis enhancement. Collectively, our ﬁndings indicate that the accumulation of CD14loCD301b+ macrophages may serve as a proangiogenic marker in adipose tissues, providing novel insights into the relationship between CD14 and obesity development.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100720"},"PeriodicalIF":5.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-12-05 DOI: 10.1016/j.jlr.2024.100721

Zihao Deng, Lixia Liu, Guantai Xie, Zhenming Zheng, Jieyou Li, Wenchong Tan, Yaotang Deng, Jinxin Zhang, Manfeng Liang, Yingxia Wu, Zhifeng Zhou, Yan Li, Yukui Chen, Yaling Huang, Hairou Su, Guibing Wu, Xiongjie Shi, Shengpei Cen, Yandan Liao, Yilin Liu, Fei Zou, Xuemei Chen

{"title":"Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma.","authors":"Zihao Deng, Lixia Liu, Guantai Xie, Zhenming Zheng, Jieyou Li, Wenchong Tan, Yaotang Deng, Jinxin Zhang, Manfeng Liang, Yingxia Wu, Zhifeng Zhou, Yan Li, Yukui Chen, Yaling Huang, Hairou Su, Guibing Wu, Xiongjie Shi, Shengpei Cen, Yandan Liao, Yilin Liu, Fei Zou, Xuemei Chen","doi":"10.1016/j.jlr.2024.100721","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100721","url":null,"abstract":"Excessive lipid accumulation promotes the occurrence and progression of hepatocellular carcinoma (HCC), accompanied by high levels of fatty acid synthetase (FASN) and more active lipogenesis. Heat shock protein 90 (Hsp90) acts as a chaperone to maintain the stability and activity of the client proteins. Studies have revealed that Hsp90 regulates the lipid metabolism of HCC, but the effect of Hsp90 on FASN still remains unknown. This study aims to discover the mechanism of Hsp90 inhibition on lipid accumulation and investigate the different effects of Hsp90 N-terminal domain inhibitor STA9090 and C-terminal domain inhibitor novobiocin (NB) on FASN protein stability and transcription pathway in HCC. We found that HCC cells tended to store lipids, which could be disrupted by Hsp90 inhibitors in vivo and in vitro. High levels of Hsp90α and FASN in tumor tissue had correlation with poor prognosis of HCC patients and Hsp90α interacted with FASN to maintain its protein stability. Furthermore, N-terminal domain of Hsp90α was essential for process of sterol regulatory element binding protein 1 (SREBP1) to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α (LXRα) to upregulate FASN transcription via LXRα/SREBP1 axis. Our data reveals that Hsp90α promotes lipid accumulation by increasing the protein stability and FASN mRNA transcription, and can be alleviated by Hsp90 inhibitors, which provides a theoretical basis for Hsp90-targeted therapy on lipid metabolism in HCC.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100721"},"PeriodicalIF":5.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791502","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

The steady-state level of Plasma Membrane Ceramide is regulated by Neutral Sphingomyelinase 2.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-12-02 DOI: 10.1016/j.jlr.2024.100719

Anne G Ostermeyer-Fay, Abhay Kanodia, Ranjana Pathak, Maria Jose Hernandez-Corbacho, Aarnoud C van der Spoel, Yusuf A Hannun, Daniel Canals

{"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":"https://doi.org/10.1016/j.jlr.2024.100719","url":null,"abstract":"During the last 30 years, an increasing number of cellular functions have been found 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.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100719"},"PeriodicalIF":5.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Porcine transient receptor potential channel 1 promotes adipogenesis and lipid deposition.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-12-02 DOI: 10.1016/j.jlr.2024.100718

Yu Fu, Xin Hao, Jingru Nie, Peng Shang, Xinxing Dong, Bo Zhang, Dawei Yan, Hao Zhang

{"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":"https://doi.org/10.1016/j.jlr.2024.100718","url":null,"abstract":"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 (Tg-pTRPC1) exhibited aggravated high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, TRPC1 may facilitate adipogenesis via activating PI3K/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.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100718"},"PeriodicalIF":5.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Predictors of plasma HDL-C concentrations in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-12-02 DOI: 10.1016/j.jlr.2024.100717

James M Shikany, John R Bassler, Jared P Reis, Pamela J Schreiner, David T Redden, John T Wilkins, Cora E Lewis

{"title":"Predictors of plasma HDL-C concentrations in the Coronary Artery Risk Development in Young Adults (CARDIA) study.","authors":"James M Shikany, John R Bassler, Jared P Reis, Pamela J Schreiner, David T Redden, John T Wilkins, Cora E Lewis","doi":"10.1016/j.jlr.2024.100717","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100717","url":null,"abstract":"HDL-C is an established risk marker for coronary heart disease. We investigated sociodemographic, lifestyle, anthropometric/physiologic, and other predictors of HDL-C over 30 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a multicenter, longitudinal cohort with a baseline exam in 1985-86 and follow-up exams at least every five years through 2016. During exams, participants completed various questionnaires, anthropometric measurements, and blood collection. We performed multiple linear regression of HDL-C at each CARDIA exam in a cross-sectional analysis, and linear mixed-effects regression to assess longitudinal change of HDL-C across exams, treating time as a linear predictor, separately in women and men. The sample size ranged from 5114 participants at baseline to 3358 at the Year 30 Exam. Just over half of participants were women and just under half were Black. Several factors were positively associated with HDL-C longitudinally in both women and men: age, self-identified Black race, alcohol intake, physical activity, and energy intake, along with sex-specific associations with current oral contraceptive use, current hormone therapy, and post-menopausal status (women only), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (men only). Other factors were inversely associated with HDL-C concentration longitudinally in both women and men: cigarette smoking, intakes of carbohydrates and total fat, body mass index, and low-density lipoprotein cholesterol and triglyceride concentrations, along with sex-specific associations with HOMA-IR and parity >0 (women only). We corroborated associations of several factors with HDL-C concentration and provided evidence of associations with several factors not extensively investigated in previous studies.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100717"},"PeriodicalIF":5.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780316","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

In Memoriam: William L. Smith, PhD.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-11-30 DOI: 10.1016/j.jlr.2024.100696

Robert C Murphy

引用次数: 0

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-11-26 DOI: 10.1016/j.jlr.2024.100716

Katherine M Ranard, Bruce Appel

{"title":"Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.","authors":"Katherine M Ranard, Bruce Appel","doi":"10.1016/j.jlr.2024.100716","DOIUrl":"10.1016/j.jlr.2024.100716","url":null,"abstract":"Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR-Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with an abnormal eye phenotype and demonstrate that even morphologically normal siblings exhibit dysregulated vision and stress response gene pathways. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities, and provide insight into maternal nutritional strategies that optimize infant brain health.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100716"},"PeriodicalIF":5.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750905","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

Glycosylation of Ceramide Synthase 6 is Required for Its Activity.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-11-26 DOI: 10.1016/j.jlr.2024.100715

Alexandra J Straus, Grace Mavodza, Can E Senkal

{"title":"Glycosylation of Ceramide Synthase 6 is Required for Its Activity.","authors":"Alexandra J Straus, Grace Mavodza, Can E Senkal","doi":"10.1016/j.jlr.2024.100715","DOIUrl":"10.1016/j.jlr.2024.100715","url":null,"abstract":"Sphingolipids play key roles in membrane structure and cellular signaling. Ceramide Synthase (CerS)-generated ceramide is implicated in cellular stress responses and induction of apoptosis. Ceramide and other sphingolipids are linked to the induction of ER stress response pathways. However, the mechanisms by which ceramide modulates ER stress signaling are not well understood. Here, we show that the ER stress inducer Brefeldin A (BFA) causes increased glycosylation of CerS6, and that treatment with BFA causes increased endogenous ceramide accumulation. To our surprise, we found that CerS6 activity was not affected by BFA-induced glycosylation. Instead, our data show that basal glycosylation of CerS6 at Asn18 is required for CerS6 activity. We used a robust HCT116 CRISPR-Cas9 CerS6 KO with reintroduction of either wild type CerS6 or a mutant CerS6 with a point mutation at asparagine-18 to an alanine (N18A) which abrogated glycosylation at that residue. Our data show that cells stably expressing the N18A mutant CerS6 had significantly lower activity in vitro and in situ as compared to WT CerS6 expressing cells. Further, the defective CerS6 with N18A mutation also had defects in GSK3β, AKT, JNK, and STAT3 signaling. Despite being required for CerS6 activity, Asn18 glycosylation did not influence ER stress response pathways. Overall, our study provides vital insight into the regulation of CerS6 activity by post-translational modification at Asn18 and identifies glycosylation of CerS6 to be important for ceramide generation and downstream cellular signaling pathways.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100715"},"PeriodicalIF":5.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750907","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

Lipid trajectories improve risk models for Alzheimer's disease and mild cognitive impairment. 血脂轨迹改进了阿尔茨海默病和轻度认知障碍的风险模型。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-11-23 DOI: 10.1016/j.jlr.2024.100714

Bruce A Chase, Roberta Frigerio, Chad J Yucus, Smita Patel, Demetrius Maraganore, Alan R Sanders, Jubao Duan, Katerina Markopoulou

{"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":"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.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100714"},"PeriodicalIF":5.0,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0