Journal of Lipid Research最新文献_第5页

NEGR1 deficiency disrupts lipid metabolism and steroidogenesis in Leydig cells, linking testosterone to behavior. NEGR1缺乏会破坏间质细胞的脂质代谢和类固醇生成，将睾酮与行为联系起来。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-29 DOI: 10.1016/j.jlr.2025.100892

Poudel Rekha, Ara Yoo, Jangrae Kim, Soojin Lee

{"title":"NEGR1 deficiency disrupts lipid metabolism and steroidogenesis in Leydig cells, linking testosterone to behavior.","authors":"Poudel Rekha, Ara Yoo, Jangrae Kim, Soojin Lee","doi":"10.1016/j.jlr.2025.100892","DOIUrl":"10.1016/j.jlr.2025.100892","url":null,"abstract":"Neuronal growth regulator 1 (NEGR1) has been identified as a critical risk factor for major depressive disorders in humans. Although NEGR1 is predominantly expressed in the brain, its deletion in mice (Negr1-/-) results in abnormalities in peripheral tissues, suggesting a role beyond the nervous system, particularly in intracellular lipid trafficking. However, the role of NEGR1 in testosterone production has not yet been elucidated. Here, we demonstrate that Negr1-/- mice exhibit significantly reduced serum and testicular testosterone levels, accompanied by diminished male reproductive behaviors. The expression of key testosterone-synthesizing enzymes was downregulated in Leydig cells, and histological analysis revealed disorganized testicular and epididymal structures with lipid droplet accumulation in testicular cells. Additionally, Negr1-/- mice displayed a significant increase in abnormal sperm morphology. Notably, testosterone supplementation alleviated their impaired sexual behaviors and mitigated anxiety- and depression-like phenotypes. These findings highlight a crucial role for NEGR1 in testicular function, particularly in testosterone production and spermatogenesis, underscoring the intricate link between hormonal balance and mental health.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100892"},"PeriodicalIF":4.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957369","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

Widespread but moderate genetic overlap between circulating polyunsaturated fatty acids and brain disorders. 循环多不饱和脂肪酸与脑部疾病之间广泛但适度的基因重叠。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-25 DOI: 10.1016/j.jlr.2025.100890

Huifang Xu, Yitang Sun, Michael Francis, Claire F Cheng, Nitya T R Modulla, J Thomas Brenna, Charleston W K Chiang, Kaixiong Ye

{"title":"Widespread but moderate genetic overlap between circulating polyunsaturated fatty acids and brain disorders.","authors":"Huifang Xu, Yitang Sun, Michael Francis, Claire F Cheng, Nitya T R Modulla, J Thomas Brenna, Charleston W K Chiang, Kaixiong Ye","doi":"10.1016/j.jlr.2025.100890","DOIUrl":"10.1016/j.jlr.2025.100890","url":null,"abstract":"Polyunsaturated fatty acids (PUFAs) are indispensable for proper neuronal function. PUFA deficiency and imbalance have been linked to various brain disorders, including major depressive disorder (MDD) and anxiety. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. We utilized genome-wide association summary statistics from six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917). We performed genome-wide analysis for each of the 120 trait pairs. We evaluated the correlation of genetic effects with genetic correlation, estimated the number of shared genetic variants with polygenic overlap, and prioritized potential causal relationships with two-sample Mendelian randomization (MR). We pinpointed specific shared variants with colocalization and statistical fine-mapping. Genetic correlation and polygenic overlap analyses revealed a widespread but moderate shared genetic basis for 77 PUFA-brain disorder trait pairs. MR suggested potential causal relationships for 16 pairs. Colocalization identified 40 shared loci (13 unique) and 22 candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2), and rs4818766 (ADARB1). These genes were mapped to lipid metabolism pathways. Integrating evidence from multiple approaches, we prioritized four PUFA-brain disorder pairs with potential causal links, including PUFA% with MDD, and omega-6% with alcohol consumption. These findings reveal a widespread but moderate shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for potential effects of PUFAs on certain brain disorders, especially MDD and alcohol consumption. Future studies are needed to elucidate potential causal effects.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100890"},"PeriodicalIF":4.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957289","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}

引用次数: 0

EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat. EBF2调节棕色脂肪的心磷脂和磷脂酰乙醇胺重塑和线粒体动力学。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-25 DOI: 10.1016/j.jlr.2025.100888

Sona Rajakumari, Soumya Jaya Divakaran

{"title":"EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat.","authors":"Sona Rajakumari, Soumya Jaya Divakaran","doi":"10.1016/j.jlr.2025.100888","DOIUrl":"10.1016/j.jlr.2025.100888","url":null,"abstract":"Mitochondria are fundamental to energy homeostasis and undergo dynamic changes in brown and beige fat. Mitochondrial dysfunctions impair thermogenic capacity and cause obesity-associated metabolic diseases. The phospholipid composition is crucial for maintaining mitochondrial function and fission-fusion processes. Here, we described early B-cell factor 2 (EBF2), a transcription factor pivotal for brown adipose tissue (BAT) development and function that regulates the integrity of mitochondrial membrane composition, function, and dynamics in brown adipocytes. Strikingly, Myf5Cre-driven targeted deletion of Ebf2 in BAT drastically reduces cardiolipin and phosphatidylethanolamine abundance and alters acyl chain remodeling of major phospholipids. BAT mitochondria of Ebf2-KO neonates exhibit a severe reduction of DRP1 and OPA1, key regulators of mitochondrial fission-fusion dynamics; further, Ebf2 deletion impairs fragmentation-fusion events in BAT. Mechanistically, EBF2 directly binds to key genes, including Srebf1, which are involved in membrane lipid metabolism and differentially regulate their expression. Also, the deletion of Ebf2 downregulates cardiolipin and phosphatidylethanolamine-synthesizing genes and accumulates phosphatidylserine and sphingomyelin levels in mitochondria. Thus, the deletion of Ebf2 perturbs the acyl chain remodeling of mitochondrial lipids and affects the fission-fusion cycle in neonatal brown adipocytes. To conclude, Ebf2 is crucial for regulating the levels and remodeling of bilayer and nonbilayer-forming lipids to conserve mitochondrial metabolism.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100888"},"PeriodicalIF":4.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957367","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

Loss of hepatic carboxylesterase 3 prevents the development of MASLD in mice. 肝羧酸酯酶3 （CES3）的丧失可阻止小鼠MASLD的发展。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-25 DOI: 10.1016/j.jlr.2025.100887

Zaid Batayneh, Xiaoli Pan, Raja Gopoju, Shuwei Hu, Shaoyu Chen, Jiayou Wang, Hui Wang, Lakshitha Gunawardana, Takhar Kasumov, Yanqiao Zhang

引用次数: 0

Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding. 抗抑郁药通过血清素增强的细胞表面结合刺激脂蛋白(a)巨量红细胞增多。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-25 DOI: 10.1016/j.jlr.2025.100889

Nikita Deo, Halima Siddiqui, Katie Peppercorn, Golnoush Madani, Alexandria Rutherford-Blyth, Malcolm Rutledge, Michael J A Williams, Sally P A McCormick, Gregory M I Redpath

{"title":"Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding.","authors":"Nikita Deo, Halima Siddiqui, Katie Peppercorn, Golnoush Madani, Alexandria Rutherford-Blyth, Malcolm Rutledge, Michael J A Williams, Sally P A McCormick, Gregory M I Redpath","doi":"10.1016/j.jlr.2025.100889","DOIUrl":"10.1016/j.jlr.2025.100889","url":null,"abstract":"We recently found that plasminogen receptors regulate the plasma membrane binding and uptake of Lp(a) via macropinocytosis. In this study, we sought to further define lipoprotein(a) [Lp(a)] macropinocytosis, discovering an unexpected role for antidepressants and serotonin in the regulation of this process. We found that the tricyclic antidepressant imipramine enhanced Lp(a) uptake, in contradiction of its published role as a macropinocytosis inhibitor. Extending these experiments to the commonly used serotonin uptake inhibitors (SSRIs) citalopram, sertraline, fluoxetine, and paroxetine, we found that citalopram and paroxetine stimulated Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) to increase uptake by macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. In contrast to Lp(a), imipramine and citalopram had no effect on low-density lipoprotein (LDL) uptake. Imipramine and serotonin increased expression of the plasminogen receptor with a C-terminal lysine (PlgRKT), a receptor known to enhance cell surface binding of Lp(a), likely accounting for their effects on Lp(a) uptake. Finally, imipramine and citalopram increased Lp(a) delivery into Rab11 recycling endosomes but not degradative pathways in the cell. These findings indicate SSRIs such as citalopram and paroxetine may have utility as a potential Lp(a)-lowering therapeutic in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100889"},"PeriodicalIF":4.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957318","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}

引用次数: 0

Alzheimer's disease disrupts intra-adipose neurovascular contact. 阿尔茨海默病破坏了脂肪内神经血管的接触。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-25 DOI: 10.1016/j.jlr.2025.100886

Michelle Kwong, Jianting Sheng, Li Yang, Stephen T C Wong

引用次数: 0

The Risk of Going Outside: Amino Phospholipids in Rheumatoid Arthritis. 外出的风险：类风湿关节炎中的氨基酸磷脂。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-20 DOI: 10.1016/j.jlr.2025.100881

Nicola Pozzi, David A Ford

引用次数: 0

Lipid and lipoprotein metabolism in microglia: Alzheimer's disease mechanisms and interventions. 小胶质细胞中的脂质和脂蛋白代谢：阿尔茨海默病的机制和干预。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-11 DOI: 10.1016/j.jlr.2025.100872

Kayla G Sprenger, Emma E Lietzke, John T Melchior, Kimberley D Bruce

{"title":"Lipid and lipoprotein metabolism in microglia: Alzheimer's disease mechanisms and interventions.","authors":"Kayla G Sprenger, Emma E Lietzke, John T Melchior, Kimberley D Bruce","doi":"10.1016/j.jlr.2025.100872","DOIUrl":"10.1016/j.jlr.2025.100872","url":null,"abstract":"Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides (TGs). Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and TG levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid droplet accumulation in microglia, reducing TG synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the CNS. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at restoring lipid handling and improving microglial function are explored. This review provides a comprehensive examination of the emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100872"},"PeriodicalIF":4.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794632","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

Integrated lipidomic and proteomic profiling reveals metabolic network disruption by SARS-CoV-2 variants. 综合脂质组学和蛋白质组学分析揭示了SARS-CoV-2变异对代谢网络的破坏。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-01 Epub Date: 2025-07-12 DOI: 10.1016/j.jlr.2025.100860

Scotland E Farley, Jennifer E Kyle, Helene Jahn, Lisa M Bramer, Paul D Piehowski, Athena A Shepmoes, Brooke Ld Kaiser, Sarai M Williams, Josie G Eder, Carsten Schultz, Fikadu G Tafesse

{"title":"Integrated lipidomic and proteomic profiling reveals metabolic network disruption by SARS-CoV-2 variants.","authors":"Scotland E Farley, Jennifer E Kyle, Helene Jahn, Lisa M Bramer, Paul D Piehowski, Athena A Shepmoes, Brooke Ld Kaiser, Sarai M Williams, Josie G Eder, Carsten Schultz, Fikadu G Tafesse","doi":"10.1016/j.jlr.2025.100860","DOIUrl":"10.1016/j.jlr.2025.100860","url":null,"abstract":"The rapid evolution of SARS-CoV-2 has produced myriad viral strains with increasing transmissibility and capacity for immune evasion. While effective vaccination campaigns have reduced the fatalities associated with SARS-CoV-2, infections continue, and a detailed understanding of how this virus manipulates host biochemical pathways remains elusive. We asked both whether the patterns of host lipid rewiring remained consistent across variants and whether the changes in the abundance of lipid classes are related to changes in the expression of the enzymes involved in their biosynthesis. We compared global nontargeted lipidomics on A549-ACE2 cells infected with the delta variant (B.1.617.2), or the omicron (B.1.1.529) variant to our previous results of global nontargeted lipidomics on A549-ACE2 cells infected with the original WA1 strain and further performed quantitative proteomics to assess changes in the host proteome. We found that metabolic rewiring, both on the lipid and the enzymatic level, is remarkably consistent across all three variants. We further mapped changes in the expression of host metabolic enzymes, linking enzyme expression to alterations in the abundance of specific lipids during infection. This analysis identified key proteins related to virus-mediated changes in lipid abundance, including fatty acid synthase (FASN), lysosomal acid lipase (LIPA), and ORMDL, a regulator of sphingolipid biosynthesis. These integrated lipidomic and proteomic experiments shed light on the importance of the complex network of host metabolism networks that support SARS-CoV-2 infection and suggest that lipid metabolism may be a promising avenue for uncovering conserved therapeutic targets.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100860"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637233","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}

引用次数: 0

Lipoprotein dynamics in neuromyelitis optica spectrum disorder. 视谱神经脊髓炎的脂蛋白动力学。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-01 Epub Date: 2025-07-21 DOI: 10.1016/j.jlr.2025.100864

Tsai-Wei Liu, Mei-Ling Cheng, Chiung-Mei Chen, Long-Sun Ro, Kuo-Hsuan Chang

{"title":"Lipoprotein dynamics in neuromyelitis optica spectrum disorder.","authors":"Tsai-Wei Liu, Mei-Ling Cheng, Chiung-Mei Chen, Long-Sun Ro, Kuo-Hsuan Chang","doi":"10.1016/j.jlr.2025.100864","DOIUrl":"10.1016/j.jlr.2025.100864","url":null,"abstract":"Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disease caused by aquaporin-4 IgG antibodies, which damage astrocytes and trigger inflammation. Although altered lipid profiles have been observed in various neuroinflammatory diseases, the role of dyslipidemia in NMOSD disease activity remains poorly understood. In this study, we analyzed plasma lipoprotein profiles in 40 patients with NMOSD during relapses, 35 patients with multiple sclerosis (MS) during relapses, and 41 age- and sex-matched healthy controls (HCs). Among 112 lipoprotein components, 39 showed significant alterations in NMOSD patients compared with both MS patients and HCs. These components exhibited consistently lower levels during relapses. Receiver operating characteristic analysis identified total apolipoprotein-A2 (Apo-A2; area under the curve [AUC] = 0.808), HDL-3-Apo-A2 (AUC = 0.806), HDL-Apo-A2 (AUC = 0.798), VLDL-2-phospholipids (PLs; AUC = 0.774), VLDL-3-PLs (AUC = 0.769), and VLDL-3-triglycerides (AUC = 0.770) as robust biomarkers for distinguishing NMOSD from HCs, whereas VLDL-3-PLs (AUC = 0.791) and HDL-3-Apo-A2 (AUC = 0.752) effectively differentiated NMOSD from MS. Importantly, HDL-4-Apo-A2 levels negatively correlated with Expanded Disability Status Scale scores (r = -0.321, P = 0.043) and spinal cord lesion length (r = -0.391, P = 0.013) in NMOSD patients. Among 22 NMOSD patients evaluated longitudinally, 36 of the 39 dysregulated lipoprotein components return to normal levels during remission. This study represents the first comprehensive lipidomic analysis in NMOSD, revealing distinct dyslipidemia patterns associated with disease activity and highlighting the potential of lipoprotein profiling as a noninvasive prognostic biomarker.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100864"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698834","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}

引用次数: 0