Journal of Lipid Research最新文献

{"title":"Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain.","authors":"Mladen Korbelik, Michal Heger, Albert W Girotti","doi":"10.1016/j.jlr.2024.100729","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100729","url":null,"abstract":"<p><p>Hydroperoxides of unsaturated membrane lipids (LOOHs) are the most abundant non-radical intermediates generated by photodynamic therapy (PDT) of soft tissues such as tumors and have far longer average lifetimes than singlet oxygen or oxygen radicals formed during initial photodynamic action. LOOH-initiated post-irradiation damage to remaining membrane lipids (chain peroxidation) or to membrane-associated proteins remains largely unrecognized. Such after-light processes could occur during clinical oncological PDT, but this is not well-perceived by practitioners of this therapy. In general, the pivotal influence of lipids in tumor responses to PDT needs to be better appreciated. Of related importance is the fact that most malignant tumors have dramatically different lipid metabolism compared with healthy tissues, and this is often ignored. The response of tumors to PDT appears especially vulnerable to manipulations within the tumor lipid microenvironment. This can be exploited for therapeutic gain with oncological PDT, as exemplified here by the combined treatment with antitumor lipid edelfosine.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100729"},"PeriodicalIF":5.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828923","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":"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":"https://doi.org/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":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3.","authors":"Majd B Protty, Victoria J Tyrrell, Ali A Hajeyah, Bethan Morgan, Daniela Costa, Yong Li, Anirban Choudhury, Rito Mitra, David Bosanquet, Alex Reed, Iuliia K Denisenko, Katsuyuki Nagata, Hideo Shindou, Benjamin F Cravatt, Alastair W Poole, Takao Shimizu, Zaheer Yousef, Peter W Collins, Valerie B O'Donnell","doi":"10.1016/j.jlr.2024.100727","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100727","url":null,"abstract":"<p><strong>Background: </strong>Enzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are pro-thrombotic. Their generation in arterial disease, and their modulation by cardiovascular therapies is unknown. Furthermore, the Lands cycle acyl-transferases that catalyze their formation are unidentified.</p><p><strong>Methods: </strong>EoxPL were measured in platelets and leukocytes from an atherosclerotic cardiovascular disease (ASCVD) cohort and retrieved human arterial thrombi from 3 anatomical sites. The impact of age, gender and aspirin was characterized in platelets from healthy subjects administered low-dose aspirin. The role of LPCAT3 in eoxPL biosynthesis was tested using an inhibitor and a cell-free assay.</p><p><strong>Results: </strong>Platelets from ASCVD patients generated lower levels of COX-derived eoxPL but elevated 12-LOX-diacyl forms, than platelets from healthy controls. This associated with aspirin and was recapitulated in healthy subjects by aspirin supplementation. P2Y12 inhibition had no impact on eoxPL. LPCAT3 inhibition selectively prevented 12-LOX-derived diacyl-eoxPL generation. LPCAT3 activity was not directly altered by aspirin. P2Y12 inhibition or aspirin had little impact on eoxPL in leukocytes. Complex aspirin-dependent gender and seasonal effects on platelet eoxPL generation were seen in healthy subjects. Limb or coronary (STEMI) thrombi displayed a platelet eoxPL signature while carotid thrombi had a white cell profile.</p><p><strong>Summary: </strong>EoxPL are altered in ASCVD by a commonly used cardiovascular therapy, and LPCAT3 was identified as the acyltransferase generating aspirin-sensitive 12-LOX diacyl forms. These changes to the phospholipid composition of blood cells in humans at risk of thrombosis may be clinically significant where the pro-coagulant membrane plays a central role in driving elevated thrombotic risk.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100727"},"PeriodicalIF":5.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824247","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":"A novel mutation, Ile344Asn, in microsomal triglyceride transfer protein abolishes binding to protein disulfide isomerase.","authors":"Swati Valmiki, Cindy Bredefeld, M Mahmood Hussain","doi":"10.1016/j.jlr.2024.100725","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100725","url":null,"abstract":"<p><p>Microsomal triglyceride transfer protein (MTP) plays crucial roles in the assembly and secretion of apolipoprotein B-containing lipoproteins and loss of function MTP variants are associated with abetalipoproteinemia, a disease characterized by the absence of these lipoproteins. MTP is a heterodimeric protein of two subunits, MTP and protein disulfide isomerase (PDI). In this study, we report a proband with abetalipoproteinemia who was monitored annually over a period of ten years in her third decade and had very low plasma lipids and undetectable apoB-containing lipoproteins. Genetic testing revealed biallelic variants in the MTTP gene. She has a well-documented nonsense mutation Gly865* that does not interact with the PDI subunit. She also has a novel missense MTP mutation, Ile344Asn. We show that this mutation abrogates lipid transfer activity in MTP and does not support apolipoprotein B secretion. This residue is present in the central α-helical domain of MTP and the substitution of Ile with Asn at this position disrupts interactions between MTP and PDI subunits. Ile344 is away from the known MTP:PDI interacting sites identified in the crystal structure of MTP suggesting that MTP:PDI interactions are more dynamic than previously envisioned. Identification of more missense mutations will enhance our understanding about the structure-function of MTP and the role of critical residues in these interactions between the two subunits. This knowledge may guide us in developing novel treatment modalities to reduce plasma lipids and atherosclerosis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100725"},"PeriodicalIF":5.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822118","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":"The Role of High Density Lipoproteins in Sepsis.","authors":"Liam R Brunham","doi":"10.1016/j.jlr.2024.100728","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100728","url":null,"abstract":"<p><p>High density lipoproteins (HDL) are best known for their role in atherosclerotic cardiovascular diseases. However, efforts to reduce cardiovascular risk by increasing the concentration of cholesterol in HDL have failed, raising the question of whether HDL may have other, more central aspects to its role in health and disease. In epidemiological studies, low levels of HDL cholesterol are strongly associated with risk of infectious diseases and death from sepsis, and during sepsis a larger decline in HDL cholesterol predicts a worse outcome. Many preclinical studies have examined strategies to augment HDL genetically or pharmacologically, and have shown that this leads to protection from sepsis in animal models. Data in humans are more limited, but suggest a clinically-relevant role of HDL in mediating the response to pathogen-associated lipids and preventing excessive inflammation. Collectively, these data raise the intriguing possibility that a clinically important biological function of HDL is as a component of the innate immune system, and suggest that pharmacological manipulation of HDL may be a strategy to reduce the organ dysfunction and death that results from uncontrolled inflammation during sepsis. In this review article, we discuss recent advances in our understanding of the role of HDL in sepsis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100728"},"PeriodicalIF":5.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822049","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":"Optical control of sphingolipid biosynthesis using photoswitchable sphingosines.","authors":"Matthijs Kol, Alexander J E Novak, Johannes Morstein, Christian Schröer, Tolulope Sokoya, Svenja Mensing, Sergei M Korneev, Dirk Trauner, Joost C M Holthuis","doi":"10.1016/j.jlr.2024.100724","DOIUrl":"10.1016/j.jlr.2024.100724","url":null,"abstract":"<p><p>Sphingolipid metabolism comprises a complex interconnected web of enzymes, metabolites and modes of regulation that influence a wide range of cellular and physiological processes. Deciphering the biological relevance of this network is challenging as numerous intermediates of sphingolipid metabolism are short-lived molecules with often opposing biological activities. Here, we introduce clickable, azobenzene-containing sphingosines, termed caSphs, as light-sensitive substrates for sphingolipid biosynthesis. Photo-isomerization of the azobenzene moiety enables reversible switching between a straight trans- and curved cis-form of the lipid's hydrocarbon tail. Combining in vitro enzyme assays with metabolic labeling studies, we demonstrate that trans-to-cis isomerization of caSphs profoundly stimulates their metabolic conversion by ceramide synthases and downstream sphingomyelin synthases. These light-induced changes in sphingolipid production rates are acute, reversible, and can be implemented with great efficiency in living cells. Our findings establish caSphs as versatile tools with unprecedented opportunities to manipulate sphingolipid biosynthesis and function with the spatiotemporal precision of light.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100724"},"PeriodicalIF":5.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822046","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":"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":"https://doi.org/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. 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. Mechanistic insights into these interventions are discussed, underscoring their potential for developing ceramide-lowering therapeutic approaches in humans.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100726"},"PeriodicalIF":5.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosphingolipids in ceramide-deficient skin lipid models.","authors":"Georgios Paraskevopoulos, Lukáš Opálka, Andrej Kováčik, Anna Paraskevopoulou, Eleni Panoutsopoulou, Irene Sagrafena, Petra Pullmannová, Robert Čáp, Kateřina Vávrová","doi":"10.1016/j.jlr.2024.100722","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100722","url":null,"abstract":"<p><p>Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5-10% SPC, which reduced permeability even compared to control with \"healthy\" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behaviour of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100722"},"PeriodicalIF":5.0,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800966","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":"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":"<p><p>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.</p>","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}

{"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":"https://doi.org/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 (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 CD14^loCD301b⁺ macrophages may serve as a proangiogenic marker in adipose tissues, 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":"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}