Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献

{"title":"Eicosapentaenoic acid inhibits cholesterol efflux pathways from cholesterol-loaded human THP-1 macrophages by reducing the hydrolysis of cholesteryl esters mediated by carboxylesterase 1","authors":"Maxime Nowak ,&nbsp;Hani Dakroub ,&nbsp;Benoît Noël ,&nbsp;Delphine Rousseau-Ralliard ,&nbsp;Sana Slimene ,&nbsp;Nathalie Abi-Saleh ,&nbsp;Morgane Benardeau ,&nbsp;Benoît Vedie ,&nbsp;Anne-Marie Cassard ,&nbsp;Jean-Louis Paul ,&nbsp;Natalie Fournier","doi":"10.1016/j.bbalip.2025.159646","DOIUrl":"10.1016/j.bbalip.2025.159646","url":null,"abstract":"<div><div>A diet high in n-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) (C20:5 n-3), is cardioprotective. PUFAs integrate into membrane phospholipids, altering membrane protein function. We investigated the effects of various PUFAs on the anti-atherogenic cholesterol efflux pathways from cholesterol-loaded human THP-1 macrophages. Cells were supplemented (or not: standard cells) with 70 μM EPA, 50 μM arachidonic acid (AA) (C20:4 n-6) or 15 μM docosahexaenoic acid (DHA) (C22:6 n-3) for an extended duration to simulate a dietary strategy. EPA led to a 13 % decrease in ABCA1-mediated cholesterol efflux and to a 17 % decrease in SR-BI/ABCG1-mediated cholesterol efflux without affecting the expression of efflux proteins, while AA and DHA showed no impact. Compared to standard cells, EPA cells exhibited higher EPA levels along with reduced AA levels. EPA cells showed increased amounts of triglycerides and cholesteryl esters (CE) without a change in the acetylated LDL uptake. EPA did not influence the phenotype of macrophages according to surface markers and released cytokines. The incorporation of EPA did not disrupt efflux in macrophages loaded with free cholesterol. Conversely, EPA decreased CE hydrolysis from lipid droplets by 22 %. The diminished cholesterol efflux was not related to triglyceride accumulation or to variations in apo E secretion. EPA reduced the expression of carboxylesterase 1 (CES1) protein by 17 % without affecting the expression of neutral cholesterol ester hydrolase 1 (NCEH1). In conclusion, the membrane incorporation of EPA hinders the cholesterol efflux pathways in THP-1 foam cells likely by impairing the CE hydrolysis mediated by carboxylesterase 1.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159646"},"PeriodicalIF":3.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of the maresin pathway and PGE2 metabolism in the failing human left ventricle","authors":"Amel Bouhadoun ,&nbsp;Hasanga D. Manikpurage ,&nbsp;Gaelle Merheb ,&nbsp;Alexandre Boutigny ,&nbsp;Marc Dubourdeau ,&nbsp;Vincent Baillif ,&nbsp;Catherine Deschildre ,&nbsp;Marylou Para ,&nbsp;Aurélie Sannier ,&nbsp;Lydia Deschamps ,&nbsp;Benjamin Richard ,&nbsp;Benoît Ho-Tin-Noé ,&nbsp;Jean-Baptiste Michel ,&nbsp;Marianne Abifadel ,&nbsp;Jean-Etienne Fabre ,&nbsp;Valérie Urbach ,&nbsp;Dan Longrois ,&nbsp;Xavier Norel","doi":"10.1016/j.bbalip.2025.159645","DOIUrl":"10.1016/j.bbalip.2025.159645","url":null,"abstract":"<div><div>Chronic inflammation is involved in the pathogenesis of heart failure (HF), with cardiac remodeling and fibrosis resulting from sustained myofibroblasts activation. This is due to an imbalance between pro-inflammatory and pro-resolving mediators including specialized pro-resolving lipid mediators (SPM). This study aimed to explore the SPM pathway and its crosstalks with other pathways in human left ventricle (LV) samples from HF-patients and non-HF donors or in <em>ex-vivo</em> cultured cardiac fibroblasts.</div><div>The SPM content was measured in LV samples from HF-patients and donors. Resolvin D5 (RvD5) and maresin-1 (MaR1) were the most abundant SPM and with similar levels between both groups, at baseline. Following exposure to exogenous DHA or EPA, SPM levels increased in both groups but MaR1 and 7(<em>S</em>)-MaR1 have shown a significantly higher increase in <em>ex-vivo</em> LV samples from HF-patients compared to donors. Furthermore, we found a higher expression of the related enzymes (lipoxygenases, LOXs): 15-LOX-1, 15-LOX-2 and 12-LOX in HF-patients LV <em>in vitro</em> samples. Finally, the MaR1 receptor (LGR6) expression was also increased in these LV samples from HF-patients compared to donors. In addition, we investigated the role of SPM on COX-2/mPGES-1/prostaglandin E₂ (PGE₂) pathway previously described as cardioprotective in HF. In cardiac fibroblasts from HF-patients, exposed to inflammatory conditions, RvD1 and MaR1 increased PGE₂ biosynthesis while RvD5 decreased it.</div><div>Taken together, our data show an enhanced MaR1 biosynthesis and functional pathway in the heart from HF-patients. Furthermore, in cultured cardiac fibroblasts, MaR1 increased the PGE₂ concentration levels. These data highlighted novel aspects of inflammation regulation in HF physiopathology.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159645"},"PeriodicalIF":3.9,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A natural thiophene from Eclipta prostrata (L.) combats obesity by enhancing adipocytes thermogenesis in high-fat diet-fed obese mice","authors":"Xiaochun Zhang,&nbsp;Chunhua Lu,&nbsp;Yuemao Shen","doi":"10.1016/j.bbalip.2025.159644","DOIUrl":"10.1016/j.bbalip.2025.159644","url":null,"abstract":"<div><div>The rising global prevalence of obesity has become a serious public health concern. Recent studies have revealed that natural products derived from medicinal plants can activate adipocytes thermogenesis, presenting promising therapeutic strategies for obesity management. <em>Eclipta prostrata</em> (L.) L., traditionally used for regulating blood glucose and lipid metabolism, has recently emerged as a potential anti-obesity herb. In this study, we identified 2,2′:5′,2″-terthiophene-5-carboxylic acid (T-CA), a naturally occurring thiophene derivative isolated from <em>Eclipta prostrata</em>, as a novel anti-obesity candidate. It enhanced thermogenesis in adipose tissue, effectively preventing and ameliorating high-fat diet (HFD)-induced obesity in mice while mitigating glucose and lipid dysregulation. Mechanistically, T-CA upregulated Perilipin 5 (Plin5), which in turn activated the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling pathway and reinforced lipid droplet (LD)–mitochondria coupling. These coordinated actions promoted mitochondrial biogenesis and fatty acid oxidation, thereby improving systemic metabolic homeostasis and enhancing resistance to diet-induced obesity. To summarize, T-CA represents an appealing approach for treating HFD-induced obesity by augmenting thermogenesis through mitochondrial activation and LD-mitochondria interactions.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159644"},"PeriodicalIF":3.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of ancient ubiquitous protein 1 (Aup1) in regulating hepatic lipid droplet levels, endoplasmic reticulum stress, and inflammation in zebrafish (Danio rerio)","authors":"Shuangyang Xu ,&nbsp;Yanan Shen ,&nbsp;Zengqi Zhao ,&nbsp;Kangsen Mai ,&nbsp;Qinghui Ai","doi":"10.1016/j.bbalip.2025.159643","DOIUrl":"10.1016/j.bbalip.2025.159643","url":null,"abstract":"<div><div>Excessive supplementation of palm oil (PO) in aquafeeds induces hepatic endoplasmic reticulum (ER) stress and inflammatory responses in fish, while lipid droplet (LD) formation has been demonstrated to alleviate stress and inflammation by sequestering lipotoxic lipids. Studies in mammals indicate that ancient ubiquitous protein 1 (Aup1) is a LD-associated protein participating in ER-associated degradation (ERAD) and LD regulation. However, whether Aup1 is involved in the regulation of hepatic LD metabolism, ER stress, and inflammatory responses has not been elucidated in fish. In this study, we cloned zebrafish (<em>Danio rerio</em>) <em>aup1</em>, conducted sequence analysis, and established <em>in vitro</em> hepatocyte models with Aup1 overexpression and knockdown through electroporation of plasmids. Bioinformatics analysis identified zebrafish Aup1 as an unstable, alkaline, hydrophilic transmembrane protein. Subcellular localization demonstrated dual localization of Aup1 on LDs and the ER. Tissue distribution experiments revealed Aup1 was ubiquitously expressed in multiple tissues, with the highest expression in the liver. RT-qPCR and Western blot showed that PO significantly upregulated Aup1 expression <em>in vivo</em> and <em>in vitro</em>, and dual-luciferase reporter assays identified Atf4a as an important transcriptional activator of zebrafish <em>aup1</em> promoter. Aup1 overexpression markedly improved LD levels as well as triglyceride (TG) content, and reduced ER stress-related genes and pro-inflammatory cytokines expression in zebrafish liver (ZFL) cells. Conversely, Aup1 knockdown exerted opposite effects. These findings indicated that Aup1 could promote LD biogenesis and mitigate ER stress and inflammation. This study may provide novel insights for developing therapeutic strategies against PO-induced hepatic damage in cultured fish species.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159643"},"PeriodicalIF":3.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor necrosis factor alpha-induced activation of SREBP2 promotes cholesterol biosynthesis in cholestasis","authors":"Ziqian Xu ,&nbsp;Xinyu Cao ,&nbsp;Zhixian Zhu,&nbsp;Jiaxin Lei,&nbsp;Ling Li,&nbsp;Xiaoxun Zhang,&nbsp;Jin Chai","doi":"10.1016/j.bbalip.2025.159642","DOIUrl":"10.1016/j.bbalip.2025.159642","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cholestasis is frequently associated with lipid metabolism disorders, elevated cholesterol levels and disruptions in bile acid homeostasis. Nevertheless, the mechanisms underlying cholesterol elevation in cholestasis remain inadequately understood. This study aims to investigate alterations in cholesterol levels and potential mechanisms in mouse models of cholestasis. Additionally, we evaluate the therapeutic potential of Sterol Regulatory Element Binding Protein 2 (SREBP2), a key transcription factor regulating cholesterol synthesis, in treating cholestasis.</div></div><div><h3>Approaches and results</h3><div>We developed mouse models of cholestasis using bile duct ligation (BDL) and a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Serum and liver samples were collected for analysis. The human hepatoma cell line PLC/RPF/5 was used for mechanistic studies. Cholestatic mice exhibited significantly elevated total cholesterol levels in serum and liver. Gene expression analysis revealed marked upregulation of cholesterol biosynthesis-related genes and the transcription factor SREBP2. Mechanistic studies indicated that TNFα promotes cholesterol synthesis by activating SREBP2 and its downstream target genes. To validate these findings in vivo, we employed the BDL mouse model and treated the mice with Fatostatin, a known SREBP2 inhibitor. Administration of Fatostatin significantly reduced serum ALT, ALP and hepatic cholesterol levels in the BDL mouse model, suggesting a potential therapeutic effect against cholestatic liver injury.</div></div><div><h3>Conclusions</h3><div>This study concludes that the activation of the NF-κB signaling pathway by TNFα leads to increased expression of SREBP2 in cholestatic mouse model. These findings indicate that the TNFα/NF-κB/SREBP2 pathway could serve as a promising target for treating cholestasis.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159642"},"PeriodicalIF":3.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144239789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in lipid research: From bench to bedside","authors":"Gwendolyn Barceló-Coblijn ,&nbsp;Jesús Balsinde","doi":"10.1016/j.bbalip.2025.159624","DOIUrl":"10.1016/j.bbalip.2025.159624","url":null,"abstract":"","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 5","pages":"Article 159624"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphoinositide acyl chain diversity: comparative analysis across species and mouse tissues","authors":"David Barneda ,&nbsp;Vishnu Janardan ,&nbsp;John Swales ,&nbsp;Maria Ciaccia ,&nbsp;Richard Goodwin ,&nbsp;Sabina Cosulich ,&nbsp;Padinjat Raghu ,&nbsp;Jonathan Clark ,&nbsp;Len Stephens ,&nbsp;Phillip Hawkins","doi":"10.1016/j.bbalip.2025.159640","DOIUrl":"10.1016/j.bbalip.2025.159640","url":null,"abstract":"<div><div>Cells create acyl chain compositions for their phosphoinositide (PIPn) pools that are distinct from other phospholipid classes. While some lower eukaryotes present highly heterogeneous PIPn (e.g., yeast, fly), more complex organisms typically display PIPn enriched in fewer molecular species (e.g., the C38:4 species in fish, frog and mice). A comprehensive analysis of murine tissues (using both LC-MS/MS and MSI) confirms a general enrichment for C38:4-PIPn but also highlights the existence of several cell populations with strikingly divergent acyl chain compositions, characterised by the prevalence of shorter-chain, more saturated species (e.g., C32:0 in the testes and C34:1 in the prostate). The evolutionary pressures driving the creation of these specific acyl chain compositions are still unclear; current evidence suggests there is probably a balance to be achieved in different cell types between the biophysical constraints imposed by PIPn as membrane-captive ‘messengers’ (e.g., flexibility in head group presentation in different membrane environments), the demand for substantial de novo lipid synthesis (e.g., in rapid membrane expansion), the need for acyl chain remodelling (e.g., in molecular segregation of functional pools) and fatty acid availability. Moreover, it would appear inevitable that this balance will be distorted under most cell culture conditions in vitro<em>.</em></div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159640"},"PeriodicalIF":3.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurogenin 2-induced central neurons generated from NPC patient-derived iPSC display attenuated neurite outgrowth while accumulating cholesterol","authors":"Miki Igarashi ,&nbsp;Takashi Miyajima ,&nbsp;Chen Wu ,&nbsp;Takeo Iwamoto ,&nbsp;Yoshikatsu Eto","doi":"10.1016/j.bbalip.2025.159639","DOIUrl":"10.1016/j.bbalip.2025.159639","url":null,"abstract":"<div><div>Niemann-Pick disease type C (NPC) is a lysosome disease hallmarked by autosomal recessive mutations in the NPC1 or NPC2 genes. It results in the accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and then induces progressive neurodegeneration in affected individuals. Previous studies have primarily used fibroblasts derived from NPC patients to examine the cellular pathology and test therapeutic agents. However, the neurodegenerative aspect of the disease should be clarified using an in vitro system that recapitulates the cellular mechanisms underlying the neuronal defects. In this study, we generated iPSCs from NPC patients, and differentiated them into neurons to examine the pathological and biological defects in NPC neurons. Five iPSCs (3 NPC and 2 healthy individuals) carrying a doxycycline-inducible NGN2 (iPSCs^TetON:NGN2) were generated, and edited cells efficiently differentiated into cortical neurons by 15 days. Although the standard differentiated culture method did not show any phenotypic features in NPC neurons, human-derived low-density lipoprotein (LDL) treatment exhibited cellular pathological features, including the accumulation of unesterified cholesterol and impaired neurite outgrowth. Miglustat, a drug approved for NPC in several countries, promoted neurite outgrowth and reduced unesterified cholesterol accumulation in LDL-treated NPC neurons. Using our model, two drugs among an FDA-approved drug library attenuated the pathological defects by LDL treatment. Collectively, our results indicate that neurons of NPC patients fail neurite extension due to suboptimal cholesterol transport to the membrane. This will be a valuable tool for NPC research to identify the pathological mechanisms of neuronal degeneration and to discover new therapeutics.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159639"},"PeriodicalIF":3.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Laminar shear stress promotes accumulation of polyunsaturated fatty acid in aortic endothelial cells through upregulation of LPCAT3 enzyme activity","authors":"Delphine Bousquet ,&nbsp;Nicolas Guillot","doi":"10.1016/j.bbalip.2025.159638","DOIUrl":"10.1016/j.bbalip.2025.159638","url":null,"abstract":"<div><h3>Objective</h3><div>Endothelial cells (ECs) play an important role in tissue homeostasis. Hemodynamic laminar shear stress are involved in both the physiological and pathological function of endothelial cells EC. Lipid metabolism has emerged as a potential regulator of EC function. Here, we aim to decipher the role of laminar shear stress in the regulation of lipid metabolism in human aortic endothelial cells.</div></div><div><h3>Approach and results</h3><div>Human aortic endothelial cells (HAOEC) were exposed to laminar shear stress, and lipid metabolism was analyzed. We found that laminar flow increased polyunsaturated fatty acid (PUFA) content in both neutral and polar lipids. These changes in fatty acid composition were dependent on lysophosphatidylcholine acyltransferase 3 (LPCAT3), which was specifically upregulated by laminar shear stress at both the mRNA and activity levels. Fatty acid uptake was also modulated by shear stress, partly <em>via</em> the LXR pathway. Notably, mechanical stimulation did not alter <em>de novo</em> fatty acid synthesis. However, fatty acid oxidation was upregulated in response to laminar shear stress, involving AMPK and ACC phosphorylation. These modifications in HAOEC fatty acid composition ultimately led to the release of a distinct pattern of lipid metabolites.</div></div><div><h3>Conclusion</h3><div>Overall these data revealed that laminar shear stress increased the turnover of FA acid and in human aortic endothelial cells through the activation of the LPCAT 3 enzyme.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 5","pages":"Article 159638"},"PeriodicalIF":3.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced cholesterol alters the biophysical properties of repaired myelin","authors":"Estephanie L. Nottar Escobar ,&nbsp;Nishama De Silva Mohotti ,&nbsp;Mara Manolescu ,&nbsp;Anika Radadiya ,&nbsp;Prajnaparamita Dhar ,&nbsp;Meredith D. Hartley","doi":"10.1016/j.bbalip.2025.159637","DOIUrl":"10.1016/j.bbalip.2025.159637","url":null,"abstract":"<div><div>The myelin sheath is a lipid-rich membrane that ensheathes axons and is required for healthy and efficient signal transduction. Myelin is damaged in neurological diseases like multiple sclerosis, but remyelination can occur through the action of oligodendrocyte precursor cells (OPCs), which differentiate into mature oligodendrocytes that wrap axons to form repaired myelin. In this study, a genetic-based mouse model of demyelination was used, which features near-complete demyelination followed by robust remyelination in the brain. Lipid mass spectrometry on isolated myelin from the remyelinated brain revealed a decrease in the percent mole fraction of cholesterol when compared to healthy myelin. Biophysical studies on monomolecular lipid films formed using repaired myelin lipid extracts showed changes in the surface behavior of the lipid films, compared to the healthy myelin lipids. Films formed using the remyelinated lipid extracts resulted in lower surface pressures and lower compressional moduli when compared to healthy controls, suggesting that repaired myelin membranes have lower lateral molecular packing within the lipid film. Synthetically prepared model membranes, based on the major lipid compositions of the healthy and diseased extracts, revealed that changes in cholesterol levels were the primary contributor to the changes in biophysical properties. Supplementation of the diseased lipid extracts with cholesterol led to a robust improvement in membrane surface pressures and compressibility. Together, these results suggest that high cholesterol levels are required for myelin membrane stability and that reduced cholesterol in repaired myelin may have a profound impact on the biophysical properties of the myelin membrane.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 5","pages":"Article 159637"},"PeriodicalIF":3.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}