Journal of Lipid Research最新文献

{"title":"DHA and EPA exacerbate hypoxia-induced ferroptosis in gastric and small intestinal mucosa by disrupting the balance between SLC7A11 upregulation and PUFA-PL accumulation.","authors":"Zhenmei Song, Xuexin Wang, Jie Zeng, Fangli Ren, Yinyin Wang, Meng Li, Qing Lin, Wenli Li, Xingchen Liao, Dezhi Wang","doi":"10.1016/j.jlr.2025.100876","DOIUrl":"10.1016/j.jlr.2025.100876","url":null,"abstract":"<p><p>Hypoxia, resulting from environmental factors or diseases, can disrupt the gastrointestinal mucosal barrier. Our previous study demonstrated that hypoxia induced ferroptosis in the gastric and small intestinal mucosa by upregulating ALOX5, NOX4, and polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). The impact of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on ferroptosis is currently a subject of debate. While DHA and EPA upregulate SLC7A11 expression, mitigating lipid peroxidation, they also elevate PUFA-PL levels, exacerbating it. This study investigated the effects and underlying mechanisms of DHA and EPA supplementation on gastric and small intestinal mucosal ferroptosis under normoxic and hypoxic conditions in vitro and in vivo. Under normoxia, DHA and EPA upregulated SLC7A11 expression through the cAMP/PKA/ATF3 pathway, thereby enhancing cellular resistance to lipid peroxidation associated with increased PUFA-PL levels and preventing ferroptosis. In contrast, under hypoxia, DHA and EPA exacerbated ferroptosis by further increasing PUFA-PL levels, which, in combination with hypoxia-induced ALOX5 and NOX4 expression, resulted in excessive lipid peroxidation that overwhelmed the protective mechanisms mediated by SLC7A11 upregulation. These findings indicate that DHA and EPA exacerbate hypoxia-induced ferroptosis in gastric and small intestinal mucosa. Therefore, individuals at risk of hypoxia should carefully consider the potential risks associated with DHA and EPA intake.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100876"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12450627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855519","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":"Corrigendum to: Functional characterization of missense variants affecting the extracellular domains of ABCA1 using a fluorescence-based assay [Journal of Lipid Research 65/1 (2024) 100482].","authors":"Marianne Teigen, Åsa Schawlann Ølnes, Katrine Bjune, Trond P Leren, Martin Prøven Bogsrud, Thea Bismo Strøm","doi":"10.1016/j.jlr.2025.100891","DOIUrl":"10.1016/j.jlr.2025.100891","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 9","pages":"100891"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957302","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":"Multiomics analysis to evaluate the enrichment of extracellular vesicles from human plasma.","authors":"Huaqi Su, Christopher Fowler, Colin L Masters, Kevin J Barnham, Gavin E Reid, Laura J Vella","doi":"10.1016/j.jlr.2025.100877","DOIUrl":"10.1016/j.jlr.2025.100877","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) in blood plasma offer a valuable reservoir of intracellular cellular cargo, making them a promising source of liquid-based biomarkers. However, the complexity of plasma, with its abundance of non-EV particles and plasma proteins, presents challenges for their molecular characterization, particular their lipid composition, using mass spectrometry-based technologies. Consequently, there is currently no comprehensive blueprint detailing both the proteomes and lipidomes of highly enriched plasma EVs. We employed an orthogonal approach using density gradient ultracentrifugation (DGUC) and size-exclusion chromatography (SEC) to isolate EVs and conducted a comparative study on four different SEC columns following DGUC to evaluate the capacity of the SEC columns in enriching EVs while depleting plasma proteins and lipoprotein particles. The EV fractions were analyzed with data-independent acquisition proteomics and nano-ESI-ultrahigh-resolution accurate mass spectrometric lipidomics. DGUC followed by the appropriated sized SEC provided the best enrichment of EVs and the corresponding depletion of plasma protein and lipoprotein particle contaminants. We show that glycerophosphoethanoamine, glycerophosphoserine, ceramide, and sphingomyelin lipids are significantly enriched, while cholesteryl ester content is significantly depleted in EVs compared to platelet depleted plasma. This strategy also enabled the detection of proteins in the enriched EV fractions with functions related to mitochondria, endosomal-autophagic-lysosomal pathways, and the central nervous system. This study highlights the benefit of depleting coisolates from plasma EV preparations to enable the detection of proteins and lipids with potential future clinical utility and underscores the need for ongoing development of improved high-throughput EV isolation technologies.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100877"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957316","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":"Defective targeting of PNPLA1 to lipid droplets causes ichthyosis in ABHD5-syndromic epidermal differentiation disorder.","authors":"Margarita Schratter, David Holubek, Lukas Koeffler, Thomas Züllig, Thomas O Eichmann, Heimo Wolinski, Monika Oberer, Achim Lass, Franz P W Radner","doi":"10.1016/j.jlr.2025.100875","DOIUrl":"10.1016/j.jlr.2025.100875","url":null,"abstract":"<p><p>ABHD5-syndromic epidermal differentiation disorder (ABHD5-sEDD; also known as Chanarin-Dorfman syndrome) is a rare autosomal recessive disorder caused by mutations in the α/β-hydrolase domain-containing 5 (ABHD5) gene, leading to systemic accumulation of neutral lipids and ichthyosis due to impaired activation of patatin-like phospholipase domain-containing (PNPLAs) proteins. While ABHD5 is a well-known co-activator of adipose triglyceride lipase (ATGL, also referred to as PNPLA2), its role in epidermal lipid metabolism is incompletely understood. Here, we identify ABHD5 as a key regulator of PNPLA1, an enzyme essential for ω-O-acylceramide (acylCer) synthesis and skin barrier formation. We analyzed seven disease-associated ABHD5 missense mutations and found that they disrupt PNPLA1 localization and function by distinct mechanisms: (i) mutations affecting the PNPLA1 binding region of ABHD5 impair PNPLA1 recruitment to intracellular lipid droplets (LDs), thus reducing acylCer synthesis; (ii) mutations in potential perilipin-binding domains of ABHD5 prevent ABHD5 association with LDs, thereby disrupting PNPLA1-LD localization. Despite these defects, restoring co-localization of ABHD5 mutants with PNPLA1 in proteoliposomes rescued full PNPLA1 enzyme activity, indicating that spatial proximity rather than direct protein binding is sufficient to facilitate acylCer formation. In summary, our findings establish a co-localization-driven model of PNPLA1 regulation, in which ABHD5 ensures proper PNPLA1 targeting to LDs and simultaneously enables its enzymatic activation. This model suggests that pharmacological strategies aimed at restoring PNPLA1 localization to LDs may represent a potential therapeutic approach for ichthyosis in ABHD5-sEDD. By elucidating the molecular mechanisms underlying disease pathogenesis, our study provides important new insights into epidermal lipid metabolism and therapeutic targeting.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100875"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862283","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":"Exchangeable APOA1 on HDL inhibits LDL binding to proteoglycans.","authors":"Esmond N Geh, Debi K Swertfeger, Isabella Roscoe, Scott E Street, Alexiana Bursey, Hannah Sexmith, Laura A Woollett, W Sean Davidson, Amy Sanghavi Shah","doi":"10.1016/j.jlr.2025.100885","DOIUrl":"10.1016/j.jlr.2025.100885","url":null,"abstract":"<p><p>The entrapment of LDLs by proteoglycans (PGs) in the extracellular matrix of the arterial intima is a key initial step in the development of atherosclerosis. HDLs can interfere with this process, but the underlying mechanism is not fully understood. The aim of this study was to investigate the mechanisms by which HDL inhibits LDL binding to PG. An In-Cell ELISA was used to measure the binding of LDL to PGs in the extracellular matrix synthesized by mouse vascular smooth muscle cells. Fast-protein liquid chromatography, immunoprecipitation, SDS-PAGE, and immunoblotting analysis were performed to characterize how HDL and its apolipoproteins inhibit LDL binding to PGs. HDL and APOA1 inhibited LDL binding to PGs in a dose-dependent manner. Competition experiments showed that HDL did not compete directly with LDL for PG binding. Instead, APOA1 dissociated from HDL and associated with LDL, reducing the ability of LDL to bind PGs. This was demonstrated by separating HDL and LDL using porous filters of different sizes and tracking the movement of either HDL or APOA1. When APOA1 was solidly anchored to HDL particles, HDL lost the ability to affect LDL-PG binding. HDL inhibits LDL binding to PGs through an interaction with its main apolipoprotein, APOA1, specifically, a pool of loosely attached, exchangeable, lipid-free APOA1 on the HDL surface. These findings identify lipid-free APOA1 as a critical mediator of the ability of HDL to reduce LDL retention in the arterial wall and provide new insights into the antiatherogenic properties of HDL.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100885"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957314","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":"Oxysterol-binding protein ORP6 regulates lipid metabolism and brain Aβ production.","authors":"Arlette A Kasongo, Viyashini Vijithakumar, Khaled S Abd-Elrahman, Radhika Prabhune, Lara Gharibeh, Rachel Nadeau, Isabelle Robillard, Shoshana Spring, Sabrina Robichaud, Shaza Asif, Derrick Gibbings, Kathryn J Moore, John G Sled, Matthieu Ruiz, Mathieu Lavallée-Adam, Stephen S G Ferguson, Baptiste Lacoste, Diane C Lagace, Mireille Ouimet","doi":"10.1016/j.jlr.2025.100868","DOIUrl":"10.1016/j.jlr.2025.100868","url":null,"abstract":"<p><p>The mammalian brain is the most cholesterol-rich organ of the body, relying on in situ de novo cholesterol synthesis. Maintaining cholesterol homeostasis is crucial for normal brain function. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic proteins that coordinate lipid homeostasis by regulating cell signaling, interorganelle membrane contact sites, and non-vesicular transport of cholesterol. Here, we show that ORP6 is highly enriched in the mammalian brain, particularly within neurons and astrocytes, with widespread expression across distinct brain regions, including the hippocampus, which is essential for learning and memory. Whole-body ablation of ORP6 (Osbpl6^-/-) in mice resulted in dysregulation of systemic and brain lipid homeostasis, with elevated levels of brain desmosterol and amyloid-beta oligomers (AβOs). Mechanistically, ORP6 knockdown in astrocytes altered the expression of cholesterol metabolism genes, promoting the accumulation of esterified cholesterol in lipid droplets, reducing cholesterol efflux and plasma membrane cholesterol content, and increasing amyloid-beta precursor protein (APP) processing. Our findings underscore the role of ORP6 in systemic and brain lipid homeostasis, highlighting its importance in maintaining overall brain health.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100868"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731807","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 risk of going outside: Amino phospholipids in rheumatoid arthritis.","authors":"Nicola Pozzi, David A Ford","doi":"10.1016/j.jlr.2025.100870","DOIUrl":"10.1016/j.jlr.2025.100870","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100870"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760328","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":"Chromatin remodeler BRD9 represses transcription of PPARα target genes, including CPT1A to suppress lipid metabolism.","authors":"Itsuki Yokoseki, Masataka Nakano, Kiamu Kurosawa, Yuichiro Higuchi, Shotaro Uehara, Nao Yoneda, Hiroshi Suemizu, Tatsuki Fukami, Miki Nakajima","doi":"10.1016/j.jlr.2025.100874","DOIUrl":"10.1016/j.jlr.2025.100874","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor α (PPARα) regulates the transcription of fatty acid oxidation-related genes, such as carnitine palmitoyltransferase 1A (CPT1A), to maintain lipid homeostasis. Recent studies have suggested the involvement of switch/sucrose non-fermentable (SWI/SNF) complexes in nuclear receptor-mediated transcription. SWI/SNF complexes are chromatin remodeling factors classified into three complexes: canonical brahma-related gene 1-/brahma-associated factor (cBAF), polybromo BAF (PBAF), and non-canonical BAF (ncBAF). Among these, the key regulator of PPARα-mediated transcription remains unclear. In this study, we sought to clarify the significance of each SWI/SNF complex in PPARα-mediated transcription. Glycerol sedimentation assay revealed that PPARα interacts with ncBAF. The expression of multiple PPARα target genes, including CPT1A, was increased in HepG2 cells or primary human hepatocytes by inhibition or knockdown of bromodomain-containing protein 9 (BRD9), a specific subunit of ncBAF. Co-immunoprecipitation and pull-down assays demonstrated that PPARα interacts with ncBAF via BRD9. Chromatin immunoprecipitation- and formaldehyde-assisted isolation of regulatory elements-qPCR analyses revealed that BI-9564, an inhibitor of BRD9, can enhance the binding of PPARα to the PPRE on CPT1A by relaxing the chromatin structure. Interestingly, lipid accumulation in free fatty acid-treated HepG2 cells was attenuated by BI-9564 treatment, and the administration of BI-9564 to mice decreased their plasma triglyceride levels. Collectively, this study demonstrated that BRD9 negatively regulates PPARα-mediated transactivation and that inhibition of BRD9 can attenuate lipid accumulation by enhancing hepatic lipid metabolism. Thus, BRD9 could be considered a novel pharmacological target for dyslipidemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100874"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804254","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":"Functional characterization of 16 variants found in the LDL receptor gene.","authors":"Kateřina Konečná, Tereza Přerovská, Tomáš Loja, Lenka Fajkusová, Jana Koutná, Michal Kramárek, Ana Catarina Alves, Mafalda Bourbon, Tomáš Freiberger, Lukáš Tichý","doi":"10.1016/j.jlr.2025.100873","DOIUrl":"10.1016/j.jlr.2025.100873","url":null,"abstract":"<p><p>Familial hypercholesterolemia (FH) is a disorder of cholesterol metabolism characterized by elevated LDL-cholesterol levels. The most common cause of FH is pathogenic variants in the LDL receptor (LDLR) gene. To shed light on the functional impact of selected LDLR variants, we functionally characterized 16 LDLR genetic variants alongside 10 control variants. We performed in vitro assays based on transient expression of WT and mutant LDLRs in LDLR-deficient Chinese hamster ovary cells. We used flow cytometry to analyze the relative amount of LDLRs expressed on the cell surface and the relative amount of internalized LDL. In addition, we analyzed the expression and maturation of LDLR protein by Western blotting. Of the 16 studied variants, two variants (p.(Asn272Thr) and p.(Arg574Leu)) did not exhibit a defect in LDLR function, one variant (p.(Ala540Thr)) exhibited a defect in LDL binding and/or internalization despite normal LDLR cell surface expression, and the remaining 13 variants had a detrimental effect on both LDLR cell surface expression and LDL internalization. The information presented in this study contributes to the clinical classification of LDLR variants and a more precise diagnosis of FH patients, highlighting the type of defect each variant produces.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100873"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794709","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":"Multiple facets of HDLs as modifiable risk factors in stroke-the good, the bad, and the ugly.","authors":"Soumya Krishnamoorthy, S Manjunatha, Deepa Damayanthi, P N Sylaja, Srinivas Gopala","doi":"10.1016/j.jlr.2025.100879","DOIUrl":"10.1016/j.jlr.2025.100879","url":null,"abstract":"<p><p>HDL as a component of the lipid profile has been extensively studied for its link to CVDs, particularly its relationship with atherogenesis. It has been observed that plasma levels of HDL-C display an inverse relationship with stroke as well, suggesting that higher levels could potentially reduce the risk of stroke. Nevertheless, recent studies suggest that HDL-C alone may not fully predict stroke risk. The complexity of HDL particles arises from their diverse nature, showing significant heterogeneity in various dimensions. The functional quality of HDL extends beyond its quantity, with factors like lipoprotein subspecies (varying in size, lipid compositions, microRNA, and protein content) influencing HDL functionality under different pathophysiological conditions. This heterogeneity of HDL, particularly in the context of stroke, has received limited attention in reviews. While some studies have suggested that higher levels of HDL-C are linked to a reduced risk of stroke, others have found no such association. While HDL is known for its atheroprotective effects, its antioxidant and anti-inflammatory properties may be as vital as cholesterol efflux in preventing atherosclerosis-related stroke. This review emphasizes the importance of exploring various functionalities of HDL in the context of stroke.By elucidating the multifaceted relationship between HDL and stroke as demonstrated by contemporary literature, we aim to enhance the understanding of HDL's influence on stroke pathophysiology and identify avenues for future research in this field.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100879"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12475846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957336","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}