Journal of Lipid Research最新文献

Daytime-restricted feeding induces lean MAFLD in high-fat diet-fed mice by upregulating CD36-mediated lipid accumulation. 白天限制喂养通过上调cd36介导的脂质积累，诱导高脂饮食喂养小鼠的瘦型MAFLD。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-23 DOI: 10.1016/j.jlr.2025.100853

Zhenyu Wang, Mingyang Zhang, Miao Chen, Shuning Fu, Yang Zhang, Mengyue Chen, Xiong Z Ruan, Yaxi Chen

{"title":"Daytime-restricted feeding induces lean MAFLD in high-fat diet-fed mice by upregulating CD36-mediated lipid accumulation.","authors":"Zhenyu Wang, Mingyang Zhang, Miao Chen, Shuning Fu, Yang Zhang, Mengyue Chen, Xiong Z Ruan, Yaxi Chen","doi":"10.1016/j.jlr.2025.100853","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100853","url":null,"abstract":"Time-restricted feeding (TRF) may aid in weight loss and improve metabolic health; however, its long-term effects and applicability to all individuals remain unclear. This study investigated the impact of different dietary patterns on hepatic metabolism by subjecting mice to either a normal chow diet or a high-fat diet, allowing for ad libitum feeding, daytime restrictive feeding (DRF), or nighttime restrictive feeding (NRF). Using metabolic cages to assess energy intake, we found that the fuel utilization rhythms of DRF mice were disrupted compared to ad libitum-fed mice. Mice on normal chow DRF exhibited only dyslipidemia, while those on high-fat DRF developed lean metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by more pronounced dyslipidemia, weight loss, and hepatic lipid accumulation. RNA seq revealed that CD36 plays a crucial role in the development of lean MAFLD induced by high-fat DRF by inhibiting AMPK phosphorylation, disrupting the balance between lipogenesis and oxidation. Mechanistic validation was performed in CD36 liver-specific knockout mice and Liposomal nanoparticles injection models. These findings provide new insights into the potential mechanisms linking feeding patterns to lean MAFLD. Additionally, CD36 emerges as a potential therapeutic target for high-fat-induced lean MAFLD. Clarifying the relationship between DRF and lean MAFLD may inform guidelines for specific populations, such as individuals practicing intermittent fasting or those working night shifts, while also suggesting potential therapeutic strategies for clinical management.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100853"},"PeriodicalIF":5.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497337","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

Modelling the post prandial CETP mediated lipid-redistribution between chylomicrons, LDL and HDL. 模拟餐后CETP介导的乳糜微粒、LDL和HDL之间的脂质再分布。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-23 DOI: 10.1016/j.jlr.2025.100847

Martin Jansen, Christine Contini, Michael M Hoffmann, Gerhard Puetz

{"title":"Modelling the post prandial CETP mediated lipid-redistribution between chylomicrons, LDL and HDL.","authors":"Martin Jansen, Christine Contini, Michael M Hoffmann, Gerhard Puetz","doi":"10.1016/j.jlr.2025.100847","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100847","url":null,"abstract":"Impaired triglyceride (TG) metabolism is associated with metabolic diseases. Non-steady state dynamics make studying postprandial lipid metabolism challenging. We already introduced a mathematical model to estimate cholesteryl ester transfer protein (CETP) mediated TG net flux in the fasting state. Here we expand this model to chylomicrons (CM) and the dynamics of postprandial lipemia. Blood samples of normolipidemic, hypertriglyceridemic (HTG) and hyperchylomicronemic volunteers were drawn at fasting and postprandial state. We separated lipoprotein-classes via classical sequential ultracentrifugation. To address CMs we developed a novel method based on Airfuge® ultracentrifugation. We studied postprandial changes of lipoproteins and their components. CETP-mediated TG redistribution was modelled based on the surface and composition data of respective lipoprotein fractions and validated by corresponding measured values. Our model estimated CETP-mediated TG flux in the fasting and postprandial state with high accuracy. Even in the postprandial condition TG net flux to LDL/HDL is dominated by VLDL. Separating CM from VLDL and modelling both fractions instead of just using the combined CM+VLDL fraction did only improve the model's accuracy slightly (by less than 7%). The proportion of ApoC3 redistributed from HDL to VLDL in postprandial lipemia is highly correlated with the change of ApoA1 in HDL2b. Our basic model is able to estimate TG redistribution via CETP among lipoproteins in postprandial lipemia of healthy and HTG subjects. An additional separation of VLDL and CM is not strictly necessary to model postprandial TG flux. Our model makes postprandial lipoprotein metabolism more tangible and may help to study lipoprotein-associated pathologies.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100847"},"PeriodicalIF":5.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497348","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

Nanodisc single-molecule pulldown to study lipid-protein interactions. 纳米盘单分子下拉研究脂质-蛋白相互作用。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-20 DOI: 10.1016/j.jlr.2025.100846

Adriana Reyes-Ordoñez, Shweta Shree, Nilmani Singh, Stephen G Sligar, Jie Chen

{"title":"Nanodisc single-molecule pulldown to study lipid-protein interactions.","authors":"Adriana Reyes-Ordoñez, Shweta Shree, Nilmani Singh, Stephen G Sligar, Jie Chen","doi":"10.1016/j.jlr.2025.100846","DOIUrl":"10.1016/j.jlr.2025.100846","url":null,"abstract":"Beyond serving structural roles in the cell membrane, many phospholipids, including phosphatidylinositol phosphates (PIPs), are key signaling molecules that regulate a myriad of cellular processes. Specific interactions with PIPs are crucial for the functions of many signaling proteins, highlighting the need for a convenient and robust method to study lipid-protein interactions. Previously we established a fluorescence microscopy-based lipid single-molecule pulldown (lipid-SiMPull) assay for detecting interactions between fluorescently tagged proteins of interest in whole-cell lysates and small unilamellar vesicles (SUVs) containing phospholipids of interest. Despite unique advantages of the lipid-SiMPull assay, SUV is not an optimal membrane model due to its instability, heterogeneity in size, and a membrane curvature inconsistent with the relative flatness of the cell membrane. Here we report the use of lipid Nanodiscs in lipid-SiMPull. Using PIP-protein pairs of known interactions, we show that Nanodiscs containing various PIPs can pull down protein targets specifically, with an estimated detection threshold of Kd in the 10-20 μM range. Remarkably, we find that each Nanodisc is bound by one copy of the protein (or protein dimer), conferring true single-molecule resolution to the assay. Transient interactions are characterized by the re-binding of proteins to individual Nanodiscs, and dissociation rates (koff) are determined from dwell time analysis. We apply this assay to interrogate structural requirements for the stability of AKT binding of PI(3,4,5)P3. Our results suggest that an intra-molecular interaction between the PH domain and kinase domain is critical for stabilizing the AKT-PI(3,4,5)P3 interaction.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100846"},"PeriodicalIF":5.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368982","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

NON-INVASIVE IDENTIFICATION OF STEATOHEPATITIS IN PATIENTS WITH MASLD USING A STEROL AND LIPIDOMIC SIGNATURE. 使用固醇和脂质组学特征对masld患者脂肪性肝炎的无创鉴定。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-20 DOI: 10.1016/j.jlr.2025.100845

Ratna Budhi Pebriana, Ting Chen, Rico J E Derks, Niek Blomberg, Aldo Grefhorst, Yassene Mohammed, Max Nieuwdorp, Joanne Verheij, Michail Doukas, Patrick C N Rensen, Adriaan G Holleboom, Maarten E Tushuizen, Martin Giera

{"title":"NON-INVASIVE IDENTIFICATION OF STEATOHEPATITIS IN PATIENTS WITH MASLD USING A STEROL AND LIPIDOMIC SIGNATURE.","authors":"Ratna Budhi Pebriana, Ting Chen, Rico J E Derks, Niek Blomberg, Aldo Grefhorst, Yassene Mohammed, Max Nieuwdorp, Joanne Verheij, Michail Doukas, Patrick C N Rensen, Adriaan G Holleboom, Maarten E Tushuizen, Martin Giera","doi":"10.1016/j.jlr.2025.100845","DOIUrl":"10.1016/j.jlr.2025.100845","url":null,"abstract":"The accumulation of cholesterol and other lipids leading to hepatic lipotoxicity drives the progression of metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), the advanced progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD). For MASH diagnosis, liver biopsy remains the reference standard, despite its invasiveness and limitations. Thus, this study aimed to find blood derived lipid markers for MASH. We investigated serum samples from 86 patients with histologically characterized MASLD, spanning the disease spectrum (i.e. 62 patients with MASL (Fibrosis grade 0-4) and 24 patients with MASH (Fibrosis grade 2-4) with a balanced distribution of hepatocellular carcinoma) and analyzed sterol composition and lipidome. To identify the presence of MASH, logistic regression was performed on each candidate either in a single or combination with various clinical parameters. Serum levels of desmosterol and phosphatidylcholine are increased in patients with MASH compared to those with MASL. After exclusion of patients using lipid lowering drugs, an increase was also found in serum levels of cholesterol, cholesterol ester, lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylethanolamine, and several individual lipid species. The ROC curve of each lipid candidate show the potential use of desmosterol, phosphatidylcholine, and a panel of lipid species in combination with alanine aminotransferase as potential diagnostic markers, characterized by a respective AUROC of 0.79 (95% CI 0.66-0.92), 0.80 (95% CI 0.64-0.97), and 0.91 (95% CI 0.82-1.00). Serum sterol and lipidome markers are characterized by strong AUROC results to distinguish with high accuracy MASH from MASL, potentially paving the way for future MASH biomarker development.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100845"},"PeriodicalIF":5.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368983","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

Optogenetic perturbation of lipid droplet localization affects lipid metabolism and development in Drosophila. 脂滴定位的光遗传扰动影响果蝇脂质代谢和发育。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-20 DOI: 10.1016/j.jlr.2025.100848

Xin Deng, Wei Wang, Dandan Peng, Luhao Zhang, Zhihao Ma, Junfen Fu, Chao Tong, Yingke Xu

{"title":"Optogenetic perturbation of lipid droplet localization affects lipid metabolism and development in Drosophila.","authors":"Xin Deng, Wei Wang, Dandan Peng, Luhao Zhang, Zhihao Ma, Junfen Fu, Chao Tong, Yingke Xu","doi":"10.1016/j.jlr.2025.100848","DOIUrl":"10.1016/j.jlr.2025.100848","url":null,"abstract":"Lipid droplets (LDs) are dynamic organelles crucial for lipid storage and homeostasis. Despite extensive documentation of their importance, the causal relationship between LD localization and function in health and disease remains inadequately understood. Here, we developed optogenetics-based tools, termed 'Opto-LDs', which facilitate the interaction between LDs and motor proteins in a light-dependent manner, enabling precise control of LD localization within cells. Utilizing these optogenetic modules, we demonstrated that light-induced relocation of LDs to the periphery of hepatocytes results in elevated very-low-density lipoprotein (VLDL) secretion, recapturing the beneficial effect of insulin in vitro. Furthermore, our studies in transgenic Drosophila revealed that proper LD localization is critical for embryonic development, with mistargeting of LDs significantly affecting egg hatching success. In summary, our work underscores the great importance of LD localization in lipid metabolism and development, and our developed tools offer valuable insights into the functions of LDs in health and disease.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100848"},"PeriodicalIF":5.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368984","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

Cyclodextrins inhibit TRPV1 and TRPA1 activation-induced nociception via cholesterol depletion. 环糊精通过胆固醇消耗抑制TRPV1和TRPA1激活诱导的伤害感受。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-16 DOI: 10.1016/j.jlr.2025.100844

Andrea Nehr-Majoros, Lajos Karakai, Maja Payrits, Noémi Bencze, Ágnes Kemény, György Sétáló, Rita Börzsei, Csaba Hetényi, Zsuzsanna Helyes, Éva Szőke

{"title":"Cyclodextrins inhibit TRPV1 and TRPA1 activation-induced nociception via cholesterol depletion.","authors":"Andrea Nehr-Majoros, Lajos Karakai, Maja Payrits, Noémi Bencze, Ágnes Kemény, György Sétáló, Rita Börzsei, Csaba Hetényi, Zsuzsanna Helyes, Éva Szőke","doi":"10.1016/j.jlr.2025.100844","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100844","url":null,"abstract":"The nociceptive Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) channels are predominantly expressed on peptidergic sensory nerves, being involved in pain sensation and neurogenic inflammation induced by local release of pro-inflammatory neuropeptides in the innervation area. Their activation is facilitated by cholesterol-rich lipid microdomains (lipid rafts) in the plasma membrane. Cyclodextrin (CD) derivatives deplete cholesterol from membrane rafts, reducing receptor activation in vitro, anticipating in vivo analgesic effects. We compared three different CD derivatives selected based on our previous results: random methylated β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin. The effects of the topical CD pretreatments were evaluated in acute pain and neurogenic vasodilatation models in mice 30 minutes after TRPV1 (resiniferatoxin) or TRPA1 (formalin or mustard oil) receptor agonist administration. Intraplantar CD pretreatments significantly reduced the duration of nocifensive behaviors during the neurogenic inflammatory phase of the formalin test, as well as mechanical, but not thermal hyperalgesia following resiniferatoxin injection. CD-pretreatment significantly reduced mustard oil-induced acute neurogenic vasodilatation in the mouse ear and decreased the total cholesterol content in the plantar skin and ear tissues. Cholesterol depletion was restored by cholesterol loaded CDs. However, overloading cells with cholesterol did not significantly affect the cholesterol depletion. In silico modeling showed that the methylated derivative RAMEB has different cholesterol binding mode compared to HPBCD and SBECD. We present the first in vivo results showing that these CD derivatives are promising agents for exerting peripheral analgesia and anti-inflammation via cholesterol depletion, also supported by our in vitro and in silico findings.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100844"},"PeriodicalIF":5.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325987","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

The origin of hydroxy-cyclohexenone fatty acids from skin barrier protein and relevance to covalent binding of ceramides. 皮肤屏障蛋白中羟基环己酮脂肪酸的来源及其与神经酰胺共价结合的关系。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-14 DOI: 10.1016/j.jlr.2025.100843

Saori Noguchi, William E Boeglin, Fumie Nakashima, Donald F Stec, M Wade Calcutt, Takuya Takeichi, Masashi Akiyama, Alan R Brash

{"title":"The origin of hydroxy-cyclohexenone fatty acids from skin barrier protein and relevance to covalent binding of ceramides.","authors":"Saori Noguchi, William E Boeglin, Fumie Nakashima, Donald F Stec, M Wade Calcutt, Takuya Takeichi, Masashi Akiyama, Alan R Brash","doi":"10.1016/j.jlr.2025.100843","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100843","url":null,"abstract":"Lipid constituents of the skin permeability barrier include a portion of ceramides and fatty acids covalently bound to the barrier protein. The covalent binding requires enzymatic oxidation of linoleate (C18:2) esterified to skin-specific acylceramides, forming a reactive 9,10-epoxy-11E-13-keto derivative. Barrier proteins treated with alkali release the bound lipids and as described recently, including two prominent cyclic linoleate derivatives, C18 hydroxy-cyclohexenone fatty acids. Herein we addressed the origin of these cyclic products by alkali treatment of potential precursors. A UV-based assay indicated the rates of Michael adduction of 9,10-epoxy-11E-13-keto to cysteine are two orders of magnitude faster than for a typical unsaturated keto fatty acid, and 10-fold faster for the dihydroxy analogue, rationalizing their biosynthesis for protein adduction. Alkali treatment degraded the epoxy-ketone and its cysteinyl (glutathione) adduct to multiple UV-absorbing products, although not including the hydroxy-cyclohexenones. By contrast, these derivatives were prominently produced from KOH treatment of the 9,10-dihydroxy-13-ketone or its glutathione adduct. As further evidence of the origin of the hydroxy-cyclohexenones, LC-MS quantitation showed a 90% reduction following KOH treatment of epidermis from mice deficient in Srd9c7, the dehydrogenase in the linoleate oxidation pathway. Taken together, the results confirm the hydroxy-cyclohexenones as derivatives of the linoleate oxidations in the skin barrier pathway and identify the dihydroxy-ketone as a component of the covalently-bonded lipids, and critical to integrity of the epidermal barrier.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100843"},"PeriodicalIF":5.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310024","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

Circulating membrane aminophospholipids contribute to thrombotic risk in rheumatoid arthritis. 循环膜氨基磷脂有助于类风湿关节炎的血栓形成风险。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-14 DOI: 10.1016/j.jlr.2025.100842

Daniela O Costa, Majd B Protty, Victoria J Tyrrell, Ali A Hajeyah, Beth Morgan, Ben Mead, Martin Giera, Peter W Collins, P Vince Jenkins, Ernest Choy, Simon A Jones, Valerie B O'Donnell

{"title":"Circulating membrane aminophospholipids contribute to thrombotic risk in rheumatoid arthritis.","authors":"Daniela O Costa, Majd B Protty, Victoria J Tyrrell, Ali A Hajeyah, Beth Morgan, Ben Mead, Martin Giera, Peter W Collins, P Vince Jenkins, Ernest Choy, Simon A Jones, Valerie B O'Donnell","doi":"10.1016/j.jlr.2025.100842","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100842","url":null,"abstract":"Patients with rheumatoid arthritis (RA) are at elevated risk of thrombotic events, yet the underlying mechanisms remain unknown. The contribution of the procoagulant membrane-surface provided by aminophospholipids (aPL) in driving thrombotic risk in RA has not been investigated. Specifically, the type of aPL exposed on circulating blood cell membranes in patients is not characterized, nor is their ability to support thrombin generation known. Here, lipidomics was used to characterize the external-facing and total levels of aPL molecular species in RA, specifically phosphatidylserine (PS) and phosphatidylethanolamine (PE) on extracellular vesicles (EVs), platelets, and white blood cells (WBC). The ability of the cells and EVs to support thrombin generation from patients and healthy controls (HC) was compared using an in vitro prothrombinase assay. RA patient plasma had significantly higher levels of thrombin-antithrombin (TAT) and D-dimers, indicating increased thrombotic activity in vivo. Higher EV and platelet counts were seen in RA, but WBC counts were not elevated. EVs from RA patients supported higher levels of thrombin generation compared to HC, while for platelets and WBC, thrombin generation was similar for both groups. EVs from RA patients also showed elevated external-facing PS molecular species, with total aPL also increased. For platelets and WBC, total and external-facing aPL levels were similar. TATs significantly correlated with EV particle counts, indicating that their circulating numbers are directly related to coagulation in vivo. Overall, our data suggest that elevated plasma EV levels in RA are a major source of pro-coagulant membranes, contributing to thrombotic risk in RA.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100842"},"PeriodicalIF":5.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310022","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

Substrate-dependent incorporation of 15-lipoxygenase products in glycerophospholipids: 15-HETE and 15-HEPE in PI, 17-HDHA in plasmalogen PE, and 13-HODE in PC. 甘油磷脂中15-脂氧合酶产物的底物依赖性掺入：PI中的15-HETE和15-HEPE， plasmalogen PE中的17-HDHA， PC中的13-HODE。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-14 DOI: 10.1016/j.jlr.2025.100841

Laura Carpanedo, Luca Marcel Wende, Bjarne Goebel, Ann-Kathrin Häfner, Michel André Chromik, Nadja Kampschulte, Dieter Steinhilber, Nils Helge Schebb

{"title":"Substrate-dependent incorporation of 15-lipoxygenase products in glycerophospholipids: 15-HETE and 15-HEPE in PI, 17-HDHA in plasmalogen PE, and 13-HODE in PC.","authors":"Laura Carpanedo, Luca Marcel Wende, Bjarne Goebel, Ann-Kathrin Häfner, Michel André Chromik, Nadja Kampschulte, Dieter Steinhilber, Nils Helge Schebb","doi":"10.1016/j.jlr.2025.100841","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100841","url":null,"abstract":"Several oxylipins including hydroxy-PUFA act as lipid mediators. In biological samples the major part occurs esterified in glycerophospholipids or other lipids. In this work, the incorporation into glycerophospholipids of 15(S)-HETE, 15(S)-HEPE, 17(S)-HDHA, and 13(S)-HODE was investigated in oxylipin-supplemented HEK293T cells and cells overexpressing 15-lipoxgenase-2 (15-LOX-2, ALOX15B). Indirect quantification of esterified oxylipins in lipid fractions showed that > 97% of each supplemented 15-LOX-2 product is esterified and that < 25% are bound to neutral lipids while > 75% are bound to distinct glycerophospholipid classes, depending on the hydroxy-PUFA. 15-HETE and 15-HEPE were found in PI/PS, while 17-HDHA was in PE and 13-HODE in PC. The same pattern was found for oxylipins endogenously formed by overexpression of 15-LOX-2. A new targeted method for the analysis of oxidized glycerophospholipids enabled to pinpoint the specific molecular species of the oxylipins. 15-HETE (20:4;15OH) and 15-HEPE (20:5;15OH) are dominantly found as PI 18:0/20:4;15OH (70%) and PI 18:0/20:5;15OH (80%), respectively. This preferential incorporation of 20:4;15OH and 20:5;15OH into PI may be biologically relevant for PI signaling pathways. In contrast, > 50% of 17-HDHA (22:6;17OH) was found in PE P-16:0/22:6;17OH, PE P-18:0/22:6;17OH, and PE P-18:1/22:6;17OH. At least 40% of 13-HODE (18:2;13OH) was incorporated into PC 16:0/18:2;13OH and relevant amounts were found in PI 18:0/18;13OH, PC 18:1/18;13OH, and PC-O 16:0/18;13OH. These results indicate that hydroxy-PUFA are bound to glycerophospholipids in a specific manner. The distinct incorporation of 15-LOX-2 products from different PUFA into glycerophospholipids might contribute to the biological effect of these oxylipins and their precursor fatty acids.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100841"},"PeriodicalIF":5.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310023","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

An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant. 基于临床相关ABCB11 E297G变异的ABCB11变异登记和新型PFIC2敲入小鼠模型

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-11 DOI: 10.1016/j.jlr.2025.100840

Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield

{"title":"An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant.","authors":"Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield","doi":"10.1016/j.jlr.2025.100840","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100840","url":null,"abstract":"Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalogue of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 non-benign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis associated ABCB11 E297G variant. BsepE297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological IBAT inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal BA excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100840"},"PeriodicalIF":5.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293872","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}

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