Prostaglandins, leukotrienes, and essential fatty acids最新文献

{"title":"Maternal blood glucose level is correlated to offspring brain fatty acid composition in a mouse model for gestational diabetes mellitus","authors":"Lidewij Schipper ,&nbsp;Noela Schaap ,&nbsp;Yixian Liu ,&nbsp;Hongyu Li ,&nbsp;Weiping Han ,&nbsp;Louise Harvey","doi":"10.1016/j.plefa.2025.102700","DOIUrl":"10.1016/j.plefa.2025.102700","url":null,"abstract":"<div><div>Gestational diabetes mellitus (GDM) may increase the risk of suboptimal neurocognitive development in infants. Maternal supply of omega-3 and -6 long chain polyunsaturated fatty acids (LCPUFAs), including eicosapentaeonic acid, docosahexaenoic acid and arachidonic acid, are critical for offspring brain development. To study the effects of GDM on offspring brain fatty acid composition, C57BL/6J mice were exposed to short-term high-fat diet feeding and low-dose streptozotocin treatments before pregnancy. Maternal blood glucose levels positively correlated to offspring brain omega 6:omega 3 ratio at postnatal day 2 and day 21, which appeared to be driven specifically by higher omega-6 LCPUFA levels. GDM may be associated with impaired brain fatty acid profile in offspring, and this may underpin altered neurodevelopmental outcomes after GDM pregnancies. These findings support further investigation into the therapeutic potential of postnatal dietary interventions targeting fatty acid status in infants born after GDM.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102700"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144885392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and dietary ALA and DHA effects on rat heart phospholipase A2 activity mediating fatty acid release and oxylipin formation have cardiovascular implications","authors":"Anne Manson ,&nbsp;Tanja Winter ,&nbsp;Harold M. Aukema","doi":"10.1016/j.plefa.2025.102697","DOIUrl":"10.1016/j.plefa.2025.102697","url":null,"abstract":"<div><div>The ways in which diet and sex influence heart phospholipase A₂ (PLA₂) activities are underexplored, particularly with respect to effects on oxylipin formation. Therefore, male and female Sprague-Dawley rats were provided diets with 1.3 % α-linolenic acid (ALA) or docosahexaenoic acid (DHA) for 6 weeks, and heart homogenates were incubated with inhibitors for secreted (s)PLA₂ (Varespladib) or calcium-independent (i)PLA₂ (methyl arachidonyl fluorophosphonate). Non-esterified polyunsaturated fatty acids (PUFA) and oxylipins were determined by HPLC-MS/MS and data were analyzed using 3-way repeated measures ANOVA. sPLA₂ activity was selective for DHA release and DHA oxylipin formation, and contributed to ∼50 % of arachidonic acid (ARA) release, but only ∼30 % of ARA oxylipin formation. Eicosapentaenoic acid (EPA) release and oxylipin formation was minor but primarily mediated by iPLA₂. iPLA₂ activity was less selective, with activity towards all measured PUFA and oxylipins, with the primary PUFA released depending on diet. For both sPLA₂ and iPLA₂, there was more activity towards DHA and its oxylipins with the DHA diet, and towards ALA and ARA and their oxylipins with the ALA diet. Sex effects on fatty acids and oxylipins differed, as DHA, EPA and ALA release were higher in females, while DGLA and cyclooxygenase-derived ARA oxylipin formation were higher in males. Interestingly, the sex effect on cyclooxygenase ARA oxylipins was attenuated with dietary DHA. These findings provide further rationale for the simultaneous measurement of PUFA and oxylipins since they are not always congruent, and shed new light on diet and sex effects on PLA₂ types in cardiovascular oxylipin biology.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102697"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid tissue composition in mice fed diets containing varying levels of Omega-3 fatty acids","authors":"Nahed Hussein ,&nbsp;Irina Dahms ,&nbsp;Norman Salem Jr.","doi":"10.1016/j.plefa.2025.102688","DOIUrl":"10.1016/j.plefa.2025.102688","url":null,"abstract":"<div><div>This study compares varying levels of dietary α-linolenic acid (ALA) as well as eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) on the fatty acid composition of multiple tissues. Two-day pregnant, C57Bl6 mice were fed through gestation and lactation with four custom made diets and the offspring were weaned to the corresponding diet: n-3 deficient (ALA, 0.07wt % of dietary fatty acids), Low ALA (0.4wt %), High ALA (5wt %), and a Low ALA enriched with DHA (2wt %) plus EPA (2wt %). The fatty acid profiles in nine tissues/organs were determined at 12 wk of age by gas chromatography. In the brain, dietary DHA+ EPA supplementation produced a slight increase in DHA but produced no effect on retina in comparison to the High ALA diet. This contrasted with liver, heart, plasma, thigh muscle where the EPA+DHA diet produced higher levels of tissue EPA and DHA compared with the ALA diets. The proportion of arachidonic acid (AA) was depressed at the DHA+ EPA intake in retina, but not brain when compared to the High ALA diet. Tissue incorporation of EPA appeared maximal for the DHA+ EPA supplementation diet, with more than a 3-fold increase in the heart when compared to the High ALA diet. The highest level of DHA was found in heart (32 %), followed by retina (27 %) in the DHA+EPA supplemented diet. These results suggest that even high levels of ALA generally cannot support the higher tissue levels of EPA or DHA found when preformed long chain n-3 PUFA are supplied in the diet.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102688"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of biological sex on skeletal muscle phospholipid membrane composition in response to omega n-3 polyunsaturated fatty acid supplementation and washout in humans","authors":"Callum J. Pufahl ,&nbsp;Sydney E. Smart ,&nbsp;Justin Bureau ,&nbsp;Brendan Ross ,&nbsp;Craig A. Simpson ,&nbsp;Adam H. Metherel ,&nbsp;James R. Dick ,&nbsp;Chris McGlory","doi":"10.1016/j.plefa.2025.102696","DOIUrl":"10.1016/j.plefa.2025.102696","url":null,"abstract":"<div><div>Omega n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with reduced inflammation, protection against cardiovascular disease, and improved cognitive function. There is also evidence that n-3 PUFA intake impacts skeletal muscle, potentially with greater effects in females than males. Sex-specific responses to n-3 PUFA intake may be linked to the incorporation of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) into skeletal muscle phospholipid membranes. However, no study has characterized the effect of biological sex on human skeletal muscle phospholipid composition in response to EPA+DHA supplementation, and washout of EPA and DHA from skeletal muscle phospholipids following the cessation of supplementation. In a repeated measures design, 15 females and 14 males consumed 5 g/d of EPA+DHA (3.75 g EPA; 1.25 g DHA) for 8 weeks followed by 14 weeks of washout. Skeletal muscle biopsies and venous blood samples were obtained at weeks 0 (baseline), 6, 8, 16, 20, and 22. Females displayed greater skeletal muscle EPA phospholipid composition (<em>p</em>= 0.035) at 6 weeks of supplementation, higher erythrocyte EPA phospholipid composition (<em>p</em>= 0.034), and whole plasma DHA composition (<em>p</em>= 0.033) compared to males. At 14 weeks of washout, skeletal muscle and erythrocyte EPA phospholipid composition (<em>p</em>&lt; 0.001 and <em>p</em>= 0.005) remained elevated above baseline, whereas whole plasma EPA composition (<em>p</em>= 0.381) was not different from baseline. We demonstrate that 5 g/d EPA+DHA supplementation influences human fatty acid composition in a manner that is both sex- and tissue-dependant.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102696"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of birth outcomes with maternal and infant FADS1 rs174547 genotypes in Japanese participants","authors":"Reiko Nita ,&nbsp;Terue Kawabata ,&nbsp;Yasuo Kagawa ,&nbsp;Kumiko Shoji ,&nbsp;Kazuhiro Nakayama ,&nbsp;Sadahiko Iwamoto ,&nbsp;Yoshiko Yanagisawa ,&nbsp;Fumiko Kimura ,&nbsp;Teruo Miyazawa ,&nbsp;Nozomi Tatsuta ,&nbsp;Takahiro Arima ,&nbsp;Nobuo Yaegashi ,&nbsp;Kunihiko Nakai","doi":"10.1016/j.plefa.2025.102683","DOIUrl":"10.1016/j.plefa.2025.102683","url":null,"abstract":"<div><div>N-3 long-chain polyunsaturated fatty acids (n-3LCPUFAs) are crucial for child growth and development particularly for fetal growth <em>in utero</em> and brain development and function. This study examined the relationship between birth outcomes and <em>FADS1</em> rs174547 genotypes in Japanese mothers and infants. The study included 406 mothers and 373 infants, i.e., 373 infant–mother pairs, from a supplementary survey of the Japan Environment and Children's Study. Multiple regression analysis revealed that infants with the CC genotype had significantly smaller head circumference at birth compared to those with the TT genotype. Moreover, an interaction between infant genotype and cord blood docosahexaenoic acid (DHA; 22:6n-3) composition affected head circumference at birth. The findings suggest that maternal and infant <em>FADS1</em> genotypes may influence fetal growth. Furthermore, in <em>FADS1</em> genotype-stratified multiple regression analysis, infants with maternal and infant CC genotypes exhibited a significant positive association between head circumference at birth and maternal erythrocyte DHA/α-linolenic acid (ALA; 18:3n-3) ratio or fish intake. We highlighted lower metabolic efficiency for endogenous long-chain polyunsaturated fatty acids synthesis in infant–mother pairs homozygous for the minor C allele of <em>FADS1</em> rs174547. In conclusion, for mothers and infants with this genetic background, maternal fish intake during pregnancy may be potentially important for fetal growth and development.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102683"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linoleic acid promotes mammary tumor growth and metastasis to brain and lung in female Balb/cJ mice","authors":"Maria Sanchez-Juarez ,&nbsp;Monica Vizcarra-Soto ,&nbsp;Rocio Castillo-Sanchez ,&nbsp;Pablo Torres-Alamilla ,&nbsp;Pedro Cortes-Reynosa ,&nbsp;Gustavo Acosta-Altamirano ,&nbsp;Monica Sierra-Martinez ,&nbsp;Eduardo Perez Salazar","doi":"10.1016/j.plefa.2025.102687","DOIUrl":"10.1016/j.plefa.2025.102687","url":null,"abstract":"<div><div>Breast cancer is the leading cause of mortality among women worldwide. The largest prevalence of breast cancer is present in high-income nations, but the incidence in low- to middle-income countries has risen in recent years, which is the consequence of various causes, such as dietary habits. Dietary fat intake is a factor associated with the risk of developing breast cancer, and a moderate positive association between n-6 fatty acids and breast cancer risk has been described. Linoleic acid (LA) is an omega-6 polyunsaturated fatty acid (PUFA), which represents an essential PUFA and the major fatty acid consumed in occidental diets. It has been demonstrated that LA promotes cellular processes involved with invasion/metastasis in MDA-MB-231 breast cancer cells. In this study, we demonstrate that LA induces migration via FFAR1 and FFAR4, invasion and secretion of matrix metalloproteinase (MMP)-2 and MMP-9 in 4T1 triple negative breast cancer cells. In addition, 4T1 cells treated with 60 µM LA for 7 days and then inoculated in Balb/cJ mice induces an increase in the weight and volume of mammary tumors, and an increase in the metastasis to brain and liver compared with Balb/cJ mice inoculated with untreated 4T1 cells. In conclusion, LA induces cellular processes involved with invasion/metastasis and an increase in the growth of mammary tumors and metastasis in a murine model of breast cancer using Balb/cJ mice and 4T1 cells.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102687"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid synthase global inducible knockout does not alter brain fatty acid concentrations but attenuates cholesterol synthesis in the adult mouse","authors":"Drew R. Seeger,&nbsp;Peddanna Kotha,&nbsp;Svetlana A. Golovko,&nbsp;Eric J. Murphy,&nbsp;Mikhail Y. Golovko","doi":"10.1016/j.plefa.2025.102679","DOIUrl":"10.1016/j.plefa.2025.102679","url":null,"abstract":"<div><div>Fatty acid (FA) <em>de novo</em> synthesis, also called <em>de novo</em> lipogenesis (DNL), has a central role in peripheral energy storage and provides structural components for lipid membranes. However, less is known regarding its contribution to brain FA homeostasis. DNL is catalyzed by fatty acid synthase (FAS), which is a multifunctional enzyme expressed in all mammalian tissues. In the present study, we addressed, for the first time, the effect of FAS gene global conditional inducible knockout (<em>Fasn</em> KO) on the adult brain FA concentrations and lipid metabolism. We achieved a 67 % reduction in the brain FAS protein levels, with a significant reduction in total FA synthesis measured by ³H₂O incorporation into FA, which was lethal 10 days after gene recombination induction. However, the concentrations of all 44 FA molecular species assayed by LC-MS were unchanged in the brain. We also did not detect changes in the major proteins involved in FA synthesis regulation and remodeling, including peroxisome proliferator-activated receptor α (PPARα), PPARδ, FA desaturase-1, -2, and -3, and Stearoyl-CoA desaturase 1 but did observe a decrease in PPARɣ levels. In addition, brain cholesterol synthesis was significantly reduced in the <em>Fasn</em> KO brains. These data indicate that DNL is not required to maintain measured FA concentrations in the brain and that dietary FA and liver-derived pools might compensate for decreased brain DNL within the duration of the study. However, our data indicate a possible role of FAS in PPARɣ regulation and cholesterol metabolism in the adult brain.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102679"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma oxylipins in children with sickle cell disease: Associations with biomarkers of inflammation and endothelial activation","authors":"BN Yamaja Setty ,&nbsp;Krishna Rao Maddipati ,&nbsp;Scott W Keith ,&nbsp;Ayako Shimada ,&nbsp;Pari Sheerer ,&nbsp;Robin E Miller","doi":"10.1016/j.plefa.2025.102670","DOIUrl":"10.1016/j.plefa.2025.102670","url":null,"abstract":"<div><div>Oxylipins are polyunsaturated fatty acid (PUFA)-derived inflammatory mediators, and include both pro-inflammatory (prostaglandins, thromboxane, leukotrienes), and pro-resolving (lipoxins, E-resolvins, D-resolvins, protectins, maresins) molecules. Sickle cell disease (SCD) is an inflammatory pathology. We profiled plasma oxylipins in SCD (<em>n</em> = 45) and control children (<em>n</em> = 24), and evaluated their associations with inflammatory biomarkers, and SCD clinical history. We demonstrated the presence of PGE2, TxB2, RvE2, RvD1, AT-RvD3, and numerous monohydroxy-PUFAs in both SCD and control plasma. Levels of TxB2, RvD1, 12-HETE, 5-HEPE, and 7-HDoHE were significantly increased in SCD. 12-HETE and 5-HEPE correlated positively with IL-6 and IL-1β, respectively, while 15-HETE negatively associated with soluble-ICAM-1. 7-HDoHE levels were significantly lower in children with a history of VOC and ACS compared to those without any clinical complications. Since RvD1 is a pro-resolving mediator, the observed increase in RvD1 in SCD may reflect a host mechanism attempting to mitigate disease-associated chronic inflammation by promoting resolution of inflammation.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102670"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid metabolism in the placentae of gestational diabetes mellitus","authors":"Nikita Joshi,&nbsp;Sadhana Joshi","doi":"10.1016/j.plefa.2025.102682","DOIUrl":"10.1016/j.plefa.2025.102682","url":null,"abstract":"<div><div>The prevalence of gestational diabetes mellitus (GDM), a metabolic complication during pregnancy is increasing rapidly. It exerts various short and long term effects on the mother and the child. Nonetheless, the mechanisms underlying the pathophysiology of GDM are still not clear. Placenta is a key ‘programming’ agent and any impairment in placental structure and function may hamper the fetal growth and development. Omega-3 and omega-6 fatty acids are key nutrients involved in placental and fetal development. The fatty acids transport from maternal circulation towards the fetus depends on the fatty acid status of the mother, fatty acid metabolism of the placenta and placental transport of fatty acids. Alteration in any of these could influence the fatty acids transport towards the fetus thereby affecting the fetal brain development and leading to impairment in cognitive function in the off-spring. We propose a role for placental fatty acid metabolism in influencing fetal growth and development which in turn can have an impact on cognitive development of the offspring born to GDM women.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102682"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans","authors":"Christopher E. Ramsden ,&nbsp;Roy G. Cutler ,&nbsp;Xiufeng Li ,&nbsp;Gregory S. Keyes","doi":"10.1016/j.plefa.2025.102681","DOIUrl":"10.1016/j.plefa.2025.102681","url":null,"abstract":"<div><div>As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with transport and protection of highly vulnerable lipids that are required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. <em>APOE</em> allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimer's disease (AD); however, the <em>specific</em> molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide-linked dimers and multimers. Here we propose the overarching hypothesis that super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of <em>APOE</em> alleles on AD risk and amyloid-β and Tau pathologies in humans. We posit that presence and abundance of Cys in human ApoE3 and ApoE2 respectively, conceal and protect vulnerable lipids transported by ApoE from peroxidation by enabling formation of disulfide-linked homo- and heteromeric ApoE complexes. We thus propose that inability to form intermolecular disulfide bridges makes ApoE4-containing lipoproteins uniquely vulnerable to peroxidation and its downstream consequences. Consistent with our model, we found that brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization and multimerization of ApoE3 and ApoE2 (but not ApoE4). By contrast, incubation with the peroxidation-resistant lipid DMPC or cholesterol alone had minimal effects on dimerization. These novel concepts and findings are integrated into our unifying model implicating peroxidation of ApoE-containing lipoproteins, with consequent ApoE receptor-ligand disruption, as initiating molecular events that ultimately lead to AD in humans.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102681"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}