Journal of Lipid Research最新文献_第2页

Dysregulation of Glu/GABA and reduction of triglycerides contribute to valproic acid-induced autism model in zebrafish. 丙戊酸诱导斑马鱼自闭症模型中Glu/GABA的失调和甘油三酯的降低。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-23 DOI: 10.1016/j.jlr.2025.100911

Qiwen Sun, Xinyi Huang, Han Long, Jianhua Guo, Ruilin Zhang, Daru Lu, Hongyan Yao, Keji Jiang, Yan Pi

{"title":"Dysregulation of Glu/GABA and reduction of triglycerides contribute to valproic acid-induced autism model in zebrafish.","authors":"Qiwen Sun, Xinyi Huang, Han Long, Jianhua Guo, Ruilin Zhang, Daru Lu, Hongyan Yao, Keji Jiang, Yan Pi","doi":"10.1016/j.jlr.2025.100911","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100911","url":null,"abstract":"Autism spectrum disorders are neurodevelopmental conditions that pose substantial diagnostic and therapeutic challenges. Maternal exposure to valproic acid (VPA) during pregnancy is a well-established risk factor associated with autism-like behaviors in offspring. This study characterized the metabolic phenotypes in the brain tissue of larval zebrafish following VPA exposure. Zebrafish were exposed to 4 μM VPA from 2 hours post-fertilization (hpf) until 4.5 days post-fertilization (dpf), and locomotor activity was assessed at 14 dpf. Comprehensive metabolomic profiling via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) identified 2,613 metabolites in brain tissue, of which 50 showed potential links to autism (CTRL_CV < 15%, VPA_CV < 20%). Significant reductions were observed in the levels of glutamine, glutamate, and triacylglycerol (TG). Nile red staining confirmed profoundly decreased TG deposition in the dorsal telencephalon (pallium), habenula, and cerebellum of VPA-exposed zebrafish. Furthermore, in vivo imaging revealed attenuated fluorescence intensity in excitatory glutamatergic and inhibitory GABAergic neurons within the habenular nucleus and optic tectum, corresponding to reduced TG levels. Conversely, the cerebellar corpus (central cerebellar body) and inferior olive nucleus exhibited an increase in excitatory glutamatergic neurons and a reduction in inhibitory GABAergic neurons, indicating an excitatory/inhibitory (E/I) imbalance. Collectively, these findings suggest that VPA may promote autism pathogenesis by disrupting the glutamine-glutamate cycle and impairing triacylglycerol metabolism in the zebrafish brain. These findings offer novel insights into metabolic dysfunction in ASD and may facilitate the identification of potential diagnostic biomarkers.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100911"},"PeriodicalIF":4.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149453","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

Carrier cross-reactivities of the bile acid reabsorption inhibitors elobixibat, linerixibat, maralixibat, and odevixibat. 胆汁酸重吸收抑制剂埃洛比西巴、利奈昔巴、马拉利西巴和奥维西巴的载体交叉反应性。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-23 DOI: 10.1016/j.jlr.2025.100910

Veronica Billo, Christopher Neelen, Marie Wannowius, Anita Neubauer, Bärbel Fühler, Yohannes Hagos, Joachim Geyer

{"title":"Carrier cross-reactivities of the bile acid reabsorption inhibitors elobixibat, linerixibat, maralixibat, and odevixibat.","authors":"Veronica Billo, Christopher Neelen, Marie Wannowius, Anita Neubauer, Bärbel Fühler, Yohannes Hagos, Joachim Geyer","doi":"10.1016/j.jlr.2025.100910","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100910","url":null,"abstract":"The bile acid reabsorption inhibitors (BARIs) elobixibat, maralixibat, and odevixibat are clinically used inhibitors of the intestinal bile acid transporter ASBT (SLC10A2). An additional BARI compound, linerixibat, is still under clinical development. In the present study, potential cross-reactivities against the closely related hepatic bile acid carrier and hepatitis B virus entry receptor NTCP (SLC10A1), as well as the steroid sulfate uptake carrier SOAT (SLC10A6) were analyzed. All BARIs potently inhibited ASBT (IC50 = 0.1-1.0 μM). Among them, elobixibat, maralixibat, and odevixibat also inhibited SOAT (IC50 = 3.2-5.9 μM) and NTCP (IC50 = 10-99 μM). Furthermore, all four BARIs inhibited the hepatic drug transporters OATP1B1, OATP1B3, and OATP2B1 (IC50 = 1.6-29 μM). Notably, ASBT inhibition by linerixibat was reversible upon washout, while maralixibat and odevixibat induced full and sustained ASBT inhibition even after removal of the inhibitor and inhibitor-free incubation over 240 min. Elobixibat and the pan-SLC10 inhibitor troglitazone revealed an intermediate effect. The ASBT S294T/I295V double mutation increased the inhibitory potency of linerixibat, suggesting a role of this domain for linerixibat binding. In contrast, this mutation had no significant effect on the ASBT inhibition by elobixibat, maralixibat, and odevixibat, indicating distinct binding sites. In conclusion, the analyzed BARIs revealed carrier cross-reactivities with NTCP, SOAT, and members of the OATP family, but behaved differently regarding their time-dependent inhibition and potential inhibitor binding sites.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100910"},"PeriodicalIF":4.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149500","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

Mitochondria-specific photorelease of ceramide induces apoptosis. 线粒体特异性神经酰胺光释放诱导细胞凋亡。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-19 DOI: 10.1016/j.jlr.2025.100907

Christian Schröer, Matthijs Kol, Anna Koch, Emely Döffinger, Murali Annamalai, Joost C M Holthuis

{"title":"Mitochondria-specific photorelease of ceramide induces apoptosis.","authors":"Christian Schröer, Matthijs Kol, Anna Koch, Emely Döffinger, Murali Annamalai, Joost C M Holthuis","doi":"10.1016/j.jlr.2025.100907","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100907","url":null,"abstract":"Deciphering the mechanisms by which bioactive intermediates of lipid metabolism influence cell behavior is a challenging task. We previously demonstrated that de novo synthesized ceramides are authentic transducers of apoptosis and that their CERT-mediated diversion to mitochondria is sufficient to initiate BAX-dependent apoptosis. To further unravel the mechanism by which mitochondrial ceramides commit cells to death, we here developed a novel mitochondria-targeted and photocaged short-chain ceramide with a clickable alkyne group for derivatization with a fluorescent reporter. We show that this compound readily and selectively accumulates inside mitochondria in a biologically inert state. Subsequent photorelease of the ceramide moiety triggered apoptosis, as evidenced by proteolytic cleavage of central components of the caspase-dependent cell death pathway. Our findings reinforce the notion that ceramides can initiate apoptotic cell death by acting directly on mitochondria and establish mitochondria-targeted photocaged ceramides as novel tools to elucidate the underlying mechanism with the spatiotemporal precision of light.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100907"},"PeriodicalIF":4.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113375","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

Targeting MGLL: Terazosin Regulates Glycerolipid Metabolism to Mitigate Endothelial Cell Senescence. 靶向mll：特拉唑嗪调节甘油脂代谢减轻内皮细胞衰老。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-17 DOI: 10.1016/j.jlr.2025.100904

Jie Huang, Jinhua Yan, Zixin Wan, Tianyi Ji, Han Li, Wukaiyang Liang, Yi Huang, Zhen Yang, Yue Xiao, Hao Nie, Cuntai Zhang

{"title":"Targeting MGLL: Terazosin Regulates Glycerolipid Metabolism to Mitigate Endothelial Cell Senescence.","authors":"Jie Huang, Jinhua Yan, Zixin Wan, Tianyi Ji, Han Li, Wukaiyang Liang, Yi Huang, Zhen Yang, Yue Xiao, Hao Nie, Cuntai Zhang","doi":"10.1016/j.jlr.2025.100904","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100904","url":null,"abstract":"Metabolic disorders often arise in senescent endothelial cells, which impair endothelial function, lead to diminished vasodilation, increased vascular stiffness, and ultimately contribute to cardiovascular disease pathogenesis. Despite notable advancements, the molecular mechanisms driving endothelial senescence and its contribution to vascular aging remain incompletely understood, thereby limiting the development of effective therapeutic strategies. Here, we investigated the protective role of terazosin (TZ) against vascular endothelial senescence using both in vivo (aged mice) and in vitro (human umbilical vein endothelial cells, HUVECs) models, combined with senescence-associated β-galactosidase (SA-β-gal) staining, lipidomics, and molecular docking simulations. TZ treatment significantly improved endothelium-dependent vasodilation, reduced vascular stiffness, and attenuated the expression of senescence markers in aged mice. Mechanistically, lipidomics revealed that TZ reduced intracellular palmitic acid (PA) accumulation in senescent endothelial cells. Furthermore, clinical observations confirmed decreased plasma PA levels and improved endothelial function in patients receiving TZ. Monoglyceride lipase (MGLL), which hydrolyzes monoglycerides into PA and glycerol, was markedly upregulated in senescent endothelial cells and aged vascular tissues. TZ directly bound to MGLL and inhibited its enzymatic activity, thereby mitigating PA-driven endothelial senescence. Collectively, these findings identify MGLL as a novel metabolic driver of endothelial senescence and establish TZ as a potential therapeutic agent for age-related vascular diseases.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100904"},"PeriodicalIF":4.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092194","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

Plasma Lipidomic Patterns Associated with Disease Activity in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (LIPID-CIDP). 慢性炎症性脱髓鞘性多根神经病变（LIPID-CIDP）与疾病活动性相关的血浆脂质组学模式

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-17 DOI: 10.1016/j.jlr.2025.100903

Kristina Auf dem Brinke, Lisa-Marie Borsch, Christian Klose, Jana Zschüntzsch, Liza Vinhoven, Manuel Nietert, Seyed Siyawasch Justus Lattau, Dirk Fitzner

{"title":"Plasma Lipidomic Patterns Associated with Disease Activity in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (LIPID-CIDP).","authors":"Kristina Auf dem Brinke, Lisa-Marie Borsch, Christian Klose, Jana Zschüntzsch, Liza Vinhoven, Manuel Nietert, Seyed Siyawasch Justus Lattau, Dirk Fitzner","doi":"10.1016/j.jlr.2025.100903","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100903","url":null,"abstract":"Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy that causes significant disability in patients. Although pathogenic mechanisms remain unclear, it is known that inflammation results in segmental demyelination. This study aims to investigate the plasma lipidomic profile of CIDP patients to identify lipid patterns associated with disease activity. Using high-throughput shotgun lipidomics, we analyzed and compared the plasma lipidome of 30 patients with CIDP (mean age ± SD: 60.7 ± 12.2 years) with that of 30 individuals diagnosed with non-demyelinating neurological disorders (OND; mean age ± SD: 52.8 ± 10.3 years). Lipids were quantified in absolute [pmol] and relative concentrations [mol%], and their levels were correlated with CIDP disease activity and clinical disability scores (R-ODS, INCAT and MRC). To control for confounders such as age and weight, strongly correlated lipids were excluded. The analysis identified 669 molecular lipid species across 15 lipid classes, revealing a significant elevation in the diacylglycerol (DAG) class in CIDP patients. Furthermore, specific lipid subspecies, including triacylglycerol (TAG), DAG, and ether-linked phosphatidylcholine (PC O-), were significantly correlated with disease activity. A set of distinct lipid subspecies, including phosphatidylcholine (PC), lyso-phosphatidylcholine (LPC), phosphatidylinositol (PI), sphingomyelin (SM), and cholesterol ester (CE) showed strong associations with clinical disability scores. These findings suggest that CIDP is characterized by distinct lipidomic profiles modulated by disease activity. This dataset could pave the way for future studies in larger cohorts evaluating the potential of plasma lipid profiles to serve as biomarkers for disease activity and severity, aiding to inform clinical management.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100903"},"PeriodicalIF":4.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092115","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

ABCG5 ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high cholesterol diet. ABCG5 - abcg8独立机制不能维持高胆固醇饮食小鼠的胆固醇平衡。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-16 DOI: 10.1016/j.jlr.2025.100902

Garrett B Anspach, Rupinder Kaur, Isha Chauhan, Erika L Savage, Brittney Poole, Victoria P Noffsinger, Xiaoming Fu, Zeneng Wang, Clarity Voy, Ryan E Temel, Scott R Gordon, Robert N Helsley, Gregory A Graf

{"title":"ABCG5 ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high cholesterol diet.","authors":"Garrett B Anspach, Rupinder Kaur, Isha Chauhan, Erika L Savage, Brittney Poole, Victoria P Noffsinger, Xiaoming Fu, Zeneng Wang, Clarity Voy, Ryan E Temel, Scott R Gordon, Robert N Helsley, Gregory A Graf","doi":"10.1016/j.jlr.2025.100902","DOIUrl":"10.1016/j.jlr.2025.100902","url":null,"abstract":"The ABCG5 ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols, but is also the primary mediator of biliary cholesterol secretion. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols remain constant, indicating the presence of an alternate pathway for cholesterol excretion. Transintestinal cholesterol elimination (TICE) is thought to compensate for biliary disruptions and G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of hepatic G5G8. Differences were not observed in fecal neutral sterols between control, acute, and chronic liver-specific G5G8 deficient mice (G5G8LKO). Cholesterol content did not differ at any point along the intestinal tract between genotypes. We also observed no change in the expression of apical or basolateral sterol transporters in the proximal small intestine. We then measured biliary and intestinal cholesterol secretion rates using cholesterol free and cholesterol enriched bile acid micelles as acceptors. While biliary cholesterol secretion was reduced, the intrinsic rate of intestinal cholesterol secretion did not differ between genotypes. G5G8LKO and whole-body G5G8-deficient mice were challenged with a cholesterol-containing diet. While control mice upregulate fecal neutral sterol excretion, G5G8-independent mechanisms fail to maintain fecal sterol excretion and oppose the accumulation of cholesterol in liver and plasma. These studies indicate that while G5G8-independent mechanisms can mediate cholesterol excretion, TICE is not upregulated in response to a loss of hepatic G5G8 and is unable to compensate for hepatic or whole-body G5G8-deficiency in response to dietary cholesterol in mice.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100902"},"PeriodicalIF":4.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086164","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

EXPRESSION OF SREBF2 AND HMGCR DISCRIMINATES THE VIABILITY OF STEATOTIC GRAFTS FOR HUMAN LIVER TRANSPLANTATION. srebf2和HMGCR的表达可区分人肝移植脂肪变性移植物的生存能力。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-16 DOI: 10.1016/j.jlr.2025.100901

Anna Baulies, Sandra Torres, Raquel Fucho, Susana Núñez, Ferran Torres, Joana Ferrer-Fàbrega, Alba Díaz, Naira Rico, Juan Carlos García-Valdecasas, Josep Fuster, Ramon Adalia, David Paredes, Antoni Rimola, José C Fernández-Checa, Carmen García-Ruiz

{"title":"EXPRESSION OF SREBF2 AND HMGCR DISCRIMINATES THE VIABILITY OF STEATOTIC GRAFTS FOR HUMAN LIVER TRANSPLANTATION.","authors":"Anna Baulies, Sandra Torres, Raquel Fucho, Susana Núñez, Ferran Torres, Joana Ferrer-Fàbrega, Alba Díaz, Naira Rico, Juan Carlos García-Valdecasas, Josep Fuster, Ramon Adalia, David Paredes, Antoni Rimola, José C Fernández-Checa, Carmen García-Ruiz","doi":"10.1016/j.jlr.2025.100901","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100901","url":null,"abstract":"Hepatic steatosis presents a raising challenge in liver transplantation (LT), yet the precise underlying players remain incompletely understood. As steatosis reflects the accumulation of several types of lipids, including cholesterol, which has emerged as a key player in metabolic-dysfunction associated fatty liver disease, our aim was to characterize the content of lipids and the expression of cholesterol metabolic genes in liver biopsies before (pre-LT) and after LT (post-LT), with the ultimate goal of identifying factors that may impact graft loss and the overall outcomes of LT. Lipid content and cholesterol-related genes in pre- and post-LT graft biopsies, clinical outcome, and survival within the first year after LT were analyzed in 174 patients. Unlike free fatty acids (FFA) and triglycerides, total and free cholesterol (FC) levels are maintained in pre- and post-LT samples. Increased FC, and FFA levels in pre-LT samples were associated with early allograft dysfunction (EAD). The increase in the expression of cholesterol regulatory genes SREBF2 and HMGCR in pre-LT samples were identified as potential risk factors of death after LT, particularly with SREBF2 whose expression associated with EAD and graft loss (GL). Collectively, these data link the expression of genes involved in the synthesis of cholesterol to LT-related mortality. These findings may translate to an increased application of marginal steatotic grafts in LT, thereby promoting a safe outcome.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100901"},"PeriodicalIF":4.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086216","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

Targeting the ARF6-dependent recycling pathway to alter lipid rafts and reduce inflammation. 靶向arf6依赖的循环途径改变脂筏和减少炎症。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-16 DOI: 10.1016/j.jlr.2025.100900

Nigora Mukhamedova, Andrew J Fleetwood, Kevin Huynh, Yangsong Xu, Tilly Van Buuren-Milne, Alexandra Faulkner, Ying Fu, Farhad Parhami, Peter J Meikle, Ilya Levental, Michael Bukrinsky, Andrew J Murphy, Dmitri Sviridov

{"title":"Targeting the ARF6-dependent recycling pathway to alter lipid rafts and reduce inflammation.","authors":"Nigora Mukhamedova, Andrew J Fleetwood, Kevin Huynh, Yangsong Xu, Tilly Van Buuren-Milne, Alexandra Faulkner, Ying Fu, Farhad Parhami, Peter J Meikle, Ilya Levental, Michael Bukrinsky, Andrew J Murphy, Dmitri Sviridov","doi":"10.1016/j.jlr.2025.100900","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100900","url":null,"abstract":"Partitioning of inflammatory receptors into lipid rafts is essential for their function, making lipid rafts a promising target for anti-inflammatory therapies. However, the practical application of lipid raft-targeted therapies has been limited by a lack of mechanistic understanding of their regulation. In this study, we demonstrate that targeting the Arf6-dependent recycling pathway effectively modifies lipid rafts and mitigates inflammation. Using Oxy210, a synthetic oxysterol, we observed significant anti-inflammatory effects both in vivo and in vitro. These effects were linked to an increased abundance of ABCA1, enhanced cholesterol efflux, and alterations in the abundance and composition of lipid rafts. Mechanistically, Oxy210 disrupted the recycling checkpoint in late endosomes by reducing the abundance and activation of the small GTPase Arf6 and decreasing PI(4,5)P2 levels. This impaired lipid raft recycling to the cell surface and simultaneously reduced ABCA1 internalization. These findings highlight a novel approach to modulating lipid raft-dependent pathological pathways, with potential applications in treating inflammation, neurodegeneration, and infectious diseases.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100900"},"PeriodicalIF":4.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086250","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

Resolving vs. Non-resolving Sphingolipid Dynamics During Macrophage Activation: A Time-resolved Metabolic Analysis. 巨噬细胞激活过程中溶解与非溶解鞘脂动力学：时间分解代谢分析。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-15 DOI: 10.1016/j.jlr.2025.100899

Nathan F Chiappa, Nidhi Lal, Edward A Botchwey

{"title":"Resolving vs. Non-resolving Sphingolipid Dynamics During Macrophage Activation: A Time-resolved Metabolic Analysis.","authors":"Nathan F Chiappa, Nidhi Lal, Edward A Botchwey","doi":"10.1016/j.jlr.2025.100899","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100899","url":null,"abstract":"Sphingolipids are increasingly recognized as critical regulators of inflammation and cell fate decisions, with metabolites such as ceramide and sphingosine 1-phosphate exerting contrasting effects on cell survival and proliferation. In macrophages, this balance is especially important, given their central role in host defense, pathogenesis and wound healing. Here, we present a time-resolved model of sphingolipid metabolism in RAW 264.7 macrophages stimulated with KdO2-Lipid A. By integrating measured metabolite concentrations with dynamic flux estimation and established enzyme kinetics, we systematically map dynamic changes in the sphingolipid network during inflammation. Our results reveal a three-phase pattern of sphingolipid remodeling that correlates with distinct functional states of the cell. Moreover, metabolites can be classified into \"resolving\" or \"non-resolving\" lipids based on whether they return to basal levels or remain dysregulated through the later phases of the inflammatory response. This partitioning suggests that targeted modulation of specific metabolic nodes may influence the resolution of inflammation. Importantly, our computational approach can assist in the rational design of experimental studies by pinpointing putative drug targets with maximal impact on sphingolipid homeostasis. Such targeted interventions may prevent the pathological amplification of inflammatory signals without globally suppressing essential sphingolipid functions. These findings highlight the utility of an integrative systems-level analysis for elucidating sphingolipid dynamics in macrophages and underscore its potential to guide therapeutic strategies against conditions involving dysregulated inflammation.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100899"},"PeriodicalIF":4.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080862","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

Advanced Alcoholic Liver Disease Driven by a Pro-ferroptotic Diet. 嗜铁饮食导致的晚期酒精性肝病

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-09-11 DOI: 10.1016/j.jlr.2025.100898

Yonggang Liang, Yanchao Xu, Megan Virostek, Ann Johnson, Bret Evers, Yaqin Deng, Yawen Meng, Jeffrey G McDonald, Philipp E Scherer, Shaojie Cui, Jin Ye

{"title":"Advanced Alcoholic Liver Disease Driven by a Pro-ferroptotic Diet.","authors":"Yonggang Liang, Yanchao Xu, Megan Virostek, Ann Johnson, Bret Evers, Yaqin Deng, Yawen Meng, Jeffrey G McDonald, Philipp E Scherer, Shaojie Cui, Jin Ye","doi":"10.1016/j.jlr.2025.100898","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100898","url":null,"abstract":"Alcoholic liver disease (ALD) encompasses a spectrum of disorders, with advanced ALD-characterized by liver fibrosis-representing a severe stage with high mortality. The NIAAA ALD mouse model, a classical approach to study ALD by delivering alcohol through the Lieber-Decarli (LD) diet, typically does not progress to advanced ALD. We previously determined that ferroptosis causes hepatocellular injury in this model. Here we speculate that the enrichment of monounsaturated fatty acids (MUFAs) and vitamin E, which inhibit ferroptosis, and the lack of the pro-ferroptotic nutrient iron in the LD diet, may limit the progression of ALD by inhibiting ferroptosis. To test this hypothesis, we modified the LD diet to generate a pro-ferroptotic LD (PFLD) diet by depleting vitamin E, increasing dietary levels of iron, and replacing MUFAs with polyunsaturated fatty acids (PUFAs) that drive ferroptosis. Upon feeding alcohol through the PFLD diet, ∼30% of the mice developed liver fibrosis and macrosteatosis, hallmarks of advanced ALD. These pathological changes were associated with exacerbated ferroptosis, possibly driven by overaccumulation of PUFA-containing triglycerides. Our findings underscore the critical role of dietary lipid composition in determining ALD severity, and demonstrate that feeding alcohol through the PFLD diet may serve as a mouse model for advanced ALD.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100898"},"PeriodicalIF":4.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058537","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