Journal of Lipid Research最新文献

{"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":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141899/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated high-density lipoprotein triglycerides increase atherosclerotic risk.","authors":"Weifang Liu, Shaoze Chen, Chengzhang Yang, Fang Lei, Xuewei Huang, Xingyuan Zhang, Tao Sun, Lijin Lin, Chuansen Wang, Yuanyuan Cao, Zhi-Gang She, Xuan Xiao, Hongliang Li","doi":"10.1016/j.jlr.2025.100791","DOIUrl":"10.1016/j.jlr.2025.100791","url":null,"abstract":"<p><p>The relationship between high-density lipoprotein (HDL) and atherosclerotic risk remains incompletely elucidated, potentially due to the inherent heterogeneity of HDL particles. Hypertriglyceridemia is associated with alterations in HDL composition. This study investigated the impact of elevated triglycerides (TG) on HDL and its association with coronary artery disease (CAD) risk using a large prospective cohort study and Mendelian randomization (MR). We found that elevated TG was associated with reduced HDL particle size, decreased concentrations of HDL components, and increased triglycerides in HDL (HDL-TG) (all P for trend < 0.001). The protective effects of HDL particle concentration and HDL cholesterol on CAD are attenuated with increasing serum TG levels. An independent and positive association between HDL-TG levels and incident CAD events (hazard ratio [HR] per 1 standard deviation increase: 1.066, 95% CI: 1.052-1.080, P < 0.001) was confirmed even after adjustment for established cardiovascular disease risk factors. MR analyses supported a causal role for HDL-TG in CAD development (inverse-variance weighted [IVW] method: odds ratios [ORs] of 1.120 (95% CI: 1.053-1.192, P < 0.001) and 1.141 (95% CI: 1.032-1.263, P = 0.010) for dataset groups 1 and 2, respectively). Drug-target MR analyses suggested a potential association between omega-3 fatty acids (OM3-FA) and lower HDL-TG levels, with LPL and DGAT2 as key pharmacological targets. Our findings suggest that elevated TG contributes to adverse alterations in HDL, elevating CAD risk. HDL-TG is an independent positive risk factor for CAD and a potential causal contributor to CAD development. OM3-FA supplementation may offer a therapeutic strategy for mitigating the CAD risk associated with elevated HDL-TG.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100791"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12088758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753101","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":"Isomerization of bis(monoacylglycero)phosphate by acyl migration.","authors":"Akira Abe, Vania Hinkovska-Galcheva, Rakesh Verma, James A Shayman","doi":"10.1016/j.jlr.2025.100789","DOIUrl":"10.1016/j.jlr.2025.100789","url":null,"abstract":"<p><p>Bis(monoacylglycero)phosphates (BMPs) are biologically functional acidic lipids present in late endosomes and lysosomes. We recently reported that lysosomal phospholipase A2 (LPLA2, PLA2G15), the lysosomal enzyme mediating BMP catabolism, degrades BMP isomers with distinct substrate specificity. Specifically, sn-(3-oleoyl-2-hydroxy)-glycerol-1-phospho-sn-1'-(3'-oleoyl-2'-hydroxy)-glycerol (S,S-(3,3'-diC_18:1)-BMP) is a significantly better substrate for LPLA2 than S,S-(2,2'-diC_18:1)-BMP. S,S-(2,2'-diC_18:1)-BMP is generally considered the only biologically relevant BMP isomer. We investigated the isomerization of S,S-(2,2'-diC_18:1)-BMP to (S,S-(3,3'-diC_18:1)-BMP) in vitro and in cells. Thin-layer chromatography was used to distinguish S,S-(3,3'-diC_18:1)-BMP from S,S-(2,2'-diC_18:1)-BMP. S,S-(2,2'-diC_18:1)-BMP/1,2-di-O-(9Z-octadecenyl)-sn-glycero-3-phosphocholine liposomes were incubated at varying pH in the presence or absence of test substances. First, we studied bovine serum albumin, which is known to promote isomerization of 1-acyl-2-lysophosphatidylcholine. The formation of S,S-(3,3'-diC_18:1)-BMP in the presence of albumin increased in a time-dependent and albumin concentration-dependent manner under neutral conditions and was dependent on pH and the molar ratio of S,S-(2,2'-diC_18:1)-BMP in liposomes. Treatment of isomeric products generated during isomerization reaction with sn-1,3-specific lipase produced both oleic acid but also lyso-phosphatidylglycerol, indicating that the conversion of S,S-(2,2'-diC_18:1)-BMP to S,S-(3,3'-diC_18:1)-BMP is preceded via S,S-(2,3'-diC_18:1)-BMP. S,S-(3,3'-diC_18:1)-BMP formed was preferentially degraded by LPLA2 over the S,S-(2,2'-diC_18:1)-BMP. Proteins such as HSP70 and human serum albumin and metal ions such as Fe³⁺ and Zn²⁺ acted as cofactors promoting the isomerization of S,S-(2,2'-diC_18:1)-BMP under neutral conditions. At baseline, RAW 264.7 cells showed nonnegligible amounts of sn-1,3-specific lipase-sensitive BMPs. However, lipase-sensitive BMPs were increased by exposure to chloroquine or NH₄Cl, suggesting that cells undergo S,S-(2,2'-diacyl)-BMP isomerization upon alkalinization of intracellular acidic compartments.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100789"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753129","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":"Introduction of a Lipidomics Scoring System for data quality assessment.","authors":"Nils Hoffmann, Robert Ahrends, Erin S Baker, Kim Ekroos, Xianlin Han, Michal Holčapek, Gerhard Liebisch, Markus R Wenk, Yu Xia, Harald C Köfeler","doi":"10.1016/j.jlr.2025.100817","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100817","url":null,"abstract":"<p><p>The scientific field of lipidomics has shown a constantly growing publication number in recent years, which is accompanied by an increasing need for quality standards. While the official shorthand nomenclature of lipids is a first and important step towards a reporting quality tool, an additional point score would reflect the quality of reported data at an even more detailed granularity. Thus, we propose a lipidomics scoring scheme that considers all the different layers of analytical information to be obtained by mass spectrometry, chromatography, and ion mobility spectrometry and awards scoring points for each of them. Furthermore, the scoring scheme is integrated with the annotation levels as proposed by the official shorthand nomenclature, with a point score, which roughly correlates with the annotated compound details. The merit of such a scoring system is the fact that it abstracts evidence for structural information into a number, which gives even the non-lipidomics expert an idea about the reporting, and by extension, data quality at first glance. Additionally, it could serve as an aid for internal quality control and for data quality assessment in the peer review process.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100817"},"PeriodicalIF":5.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029829","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":"SDCCAG3 inhibits adipocyte hypertrophy and improves obesity-related metabolic disorders via SDCCAG3/SMURF1/PPARγ axis.","authors":"Fenglei Huo, Chenghang Liu, Xi Wang, Jinzheng Li, Zhifeng Wang, Duanqin Liu, Weipeng Lan, Xingyan Zhu, Jing Lan","doi":"10.1016/j.jlr.2025.100772","DOIUrl":"10.1016/j.jlr.2025.100772","url":null,"abstract":"<p><p>Obesity is a prevalent global disease associated with various metabolic disorders. The expansion of white adipose tissue plays a pivotal role in regulating obesity-related metabolic dysfunctions. This study identified serum-defined colon cancer antigen 3 (SDCCAG3) as a novel key modulator of adipocyte metabolism. In adipose-specific SDCCAG3 knockout mice fed a high-fat diet, pathological expansion of adipose tissue, impaired glucose tolerance, insulin resistance, increased inflammatory markers, and augmented hepatic lipid accumulation were observed. Conversely, obesity models by specific overexpression of SDCCAG3 in adipose tissue confirmed that SDCCAG3 alleviated pathological expansion of adipose tissue, improved obesity-related metabolic disorders, with no observed changes in adipose tissue development under normal dietary conditions. Mechanistically, SDCCAG3 enhanced the stability of peroxisome proliferator-activated receptor gamma (PPARγ) by preventing its degradation via the ubiquitin-proteasome system through the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1). Additionally, SDCCAG3 was subjected to negative transcriptional regulation by PPARγ, forming a SDCCAG3-PPARγ-SDCCAG3 loop that enhanced adipocyte lipid metabolism. Collectively, these findings demonstrated that SDCCAG3 functioned as a beneficial positive regulator of adipose tissue expansion and metabolic homeostasis, indicating its potential as a therapeutic target for metabolic diseases associated with nutrient excess.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100772"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585984","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":"Palmitic acid alters enhancers/super-enhancers near inflammatory and efferocytosis-associated genes in human monocytes.","authors":"Vinay Singh Tanwar, Marpadga A Reddy, Suchismita Dey, Vajir Malek, Linda Lanting, Zhuo Chen, Rituparna Ganguly, Rama Natarajan","doi":"10.1016/j.jlr.2025.100774","DOIUrl":"10.1016/j.jlr.2025.100774","url":null,"abstract":"<p><p>Free fatty acids like palmitic acid (PA) are elevated in obesity and diabetes and dysregulate monocyte and macrophage functions, contributing to enhanced inflammation in these cardiometabolic diseases. Epigenetic mechanisms regulating enhancer functions play key roles in inflammatory gene expression, but their role in PA-induced monocyte/macrophage dysfunction is unknown. We found that PA treatment altered the epigenetic landscape of enhancers and super-enhancers (SEs) in human monocytes. Integration with RNA-seq data revealed that PA-induced enhancers/SEs correlated with PA-increased expression of inflammatory and immune response genes, while PA-inhibited enhancers correlated with downregulation of phagocytosis and efferocytosis genes. These genes were similarly regulated in macrophages from mouse models of diabetes and accelerated atherosclerosis, human atherosclerosis, and infectious agents. PA-regulated enhancers/SEs harbored SNPs associated with diabetes, obesity, and body mass index indicating disease relevance. We verified increased chromatin interactions between PA-regulated enhancers/SEs and inflammatory gene promoters and reduced interactions at efferocytosis genes. PA-induced gene expression was reduced by inhibitors of BRD4, and NF-κB. PA treatment inhibited phagocytosis and efferocytosis in human macrophages. Together, our findings demonstrate that PA-induced enhancer dynamics at key monocyte/macrophage enhancers/SEs regulate inflammatory and immune genes and responses. Targeting these PA-regulated epigenetic changes could provide novel therapeutic opportunities for cardiometabolic disorders.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100774"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605189","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":"Inflammatory markers after supplementation with marine n-3 or plant n-6 PUFAs: A randomized double-blind crossover study.","authors":"Elise Grytten, Johnny Laupsa-Borge, Kaya Cetin, Pavol Bohov, Jan Erik Nordrehaug, Jon Skorve, Rolf K Berge, Elin Strand, Bodil Bjørndal, Ottar K Nygård, Espen Rostrup, Gunnar Mellgren, Simon N Dankel","doi":"10.1016/j.jlr.2025.100770","DOIUrl":"10.1016/j.jlr.2025.100770","url":null,"abstract":"<p><p>Omega-3 (n-3) (e.g., EPA/DHA) and omega-6 (n-6) (e.g., linoleic acid [LA]) FAs are suggested to have opposite effects on inflammation, but results are inconsistent and direct comparisons of n-3 and n-6 are lacking. In a double-blind, randomized, and crossover study, females (n = 16) and males (n = 23) aged 30-70 years with abdominal obesity were supplemented with 3-4 g/d EPA/DHA (fish oil) or 15-20 g/d LA (safflower oil) for 7 weeks, with a 9-week washout phase. Cytokines and chemokines (multiplex assay), acute-phase proteins (MALDI-TOF mass spectrometry), endothelial function (vascular reaction index), blood pressure, FA composition (red blood cell membranes/serum/adipose tissue, GC-MS/MS), and adipose gene expression (microarrays, quantitative PCR) were measured. While significant differences between treatments in relative change scores were found for systolic blood pressure (n-3 vs. n-6: -1.81% vs. 2.61%, P = 0.003), no differences between n-3 and n-6 were found for any circulatory inflammatory markers. However, compared with baseline, n-3 was followed by reductions in circulating TNF (-24.9%, P < 0.001), regulated upon activation, normal T cell expressed and secreted (-12.1%, P < 0.001), and macrophage inflammatory protein 1-beta (-12.5%, P = 0.014), and n-6 by lowered TNF (-18.8%, P < 0.001), regulated upon activation, normal T cell expressed and secreted (-7.37%, P = 0.027), monocyte chemoattractant protein-1 (-7.81%, P = 0.020), and macrophage inflammatory protein 1-beta (-14.2%, P = 0.010). Adipose tissue showed significant treatment differences in weight percent of EPA (n-3 vs. n-6: 50.2%∗ vs. -1.38%, P < 0.001, ∗: significant within-treatment change score), DHA (16.0%∗ vs. -3.67%, P < 0.001), and LA (-0.033 vs. 4.91%∗, P < 0.001). Adipose transcriptomics revealed overall downregulation of genes related to inflammatory processes after n-3 and upregulation after n-6, partly correlating with changes in circulatory markers. These data point to tissue-specific proinflammatory effects of high n-6 intake, but a net systemic anti-inflammatory effect as for n-3.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100770"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585972","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":"Hexokinase 2 promotes ISGylation of Acyl-CoA synthetase long-chain family member 4 in sepsis-induced microglia cells.","authors":"Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling","doi":"10.1016/j.jlr.2025.100776","DOIUrl":"10.1016/j.jlr.2025.100776","url":null,"abstract":"<p><p>Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100776"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630355","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":"Spatial characterization of RPE structure and lipids in the PEX1-p.Gly844Asp mouse model for Zellweger spectrum disorder.","authors":"Samy Omri, Catherine Argyriou, Rachel S Pryce, Erminia Di Pietro, Pierre Chaurand, Nancy Braverman","doi":"10.1016/j.jlr.2025.100771","DOIUrl":"10.1016/j.jlr.2025.100771","url":null,"abstract":"<p><p>Zellweger Spectrum Disorder (ZSD) is caused by defects in PEX genes, whose proteins are required for peroxisome assembly and function. Peroxisome dysfunction in ZSD causes multisystem effects, with progressive retinal degeneration (RD) among the most frequent clinical findings. However, much remains unknown about how peroxisome deficiency causes RD. To study RD pathophysiology in ZSD, we used the PEX1-p.Gly844Asp (G844D) mouse model, which represents the common human PEX1-p.Gly843Asp (G843D) variant. We previously reported diminished retinal function, diminished functional vision, and neural retina structural defects in this model. Here, we investigate the retinal pigment epithelium (RPE) phenotype, examining morphological, inflammatory, and lipid changes at 1, 3, and 6 months of age. We report that RPE cells exhibit evident degeneration by 3 months that worsens with time, starts in the dorsal pole, and is accompanied by subretinal inflammatory cell infiltration. We match these events with imaging mass spectrometry for regional analysis of lipids in the RPE. We identified 47 lipid alterations preceding structural changes, 9 of which localize to the dorsal pole. 29 of these persist to 3 months, with remodeling of the dorsal pole lipid signature. 13 new alterations occur concurrent with histological changes. Abnormalities in peroxisome-dependent lipids detected by LC/MS/MS are exacerbated over time. This study represents the first characterization of RPE in a ZSD model, and the first in situ lipid analysis in peroxisome-deficient tissue. Our findings uncover potential lipid drivers of RD progression in ZSD, and identify candidate biomarkers for retinopathy progression and response to therapy.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100771"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585987","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 reaction specificity of mammalian ALOX15B orthologs does not depend on the evolutionary ranking of the animals.","authors":"Eda Gündem, Sabine Stehling, Astrid Borchert, Hartmut Kuhn","doi":"10.1016/j.jlr.2025.100768","DOIUrl":"10.1016/j.jlr.2025.100768","url":null,"abstract":"<p><p>Arachidonic acid lipoxygenases (ALOXs) play important roles in cell differentiation and in the pathogenesis of cardiovascular, hyperproliferative, neurodegenerative, and metabolic diseases. The human genome involves six intact ALOX genes and knockout studies of the corresponding mouse orthologs indicated that the coding multiplicity of ALOX isoforms is not an indication for functional redundancy. Despite their evolutionary relatedness human and mouse ALOX15 and ALOX15B orthologs exhibit different catalytic properties. Human ALOX15 oxygenates arachidonic acid mainly to 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid but 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid is the dominant oxygenation product of mouse Alox15. This functional difference is the results of a targeted enzyme evolution but the driving forces for this process have not been well defined. For human and mouse ALOX15B orthologs similar functional differences have been reported but for the time being it was unclear whether these differences might also be a consequence of targeted enzyme evolution. To address this question, we systematically searched the public databases for ALOX15B genes, expressed selected enzymes, and characterized their functional properties. We found that functional ALOX15B genes frequently occur in Prototheria and Eutheria but orthologous genes are rare in Metatheria. The vast majority of mammalian ALOX15B orthologs constitute arachidonic acid 15-lipoxygenating enzymes and this property did not depend on the evolutionary ranking of the animals. Only several Muridae species including M. musculus, M. pahari, M. caroli, M. coucha, and A. niloticus express arachidonic acid 8-lipoxygenating ALOX15B orthologs. Consequently, the difference in the reaction specificity of mouse and human ALOX15B orthologs may not be considered a functional consequence of targeted enzyme evolution.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100768"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567403","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}