Journal of Lipid Research最新文献_第2页

Elevated levels of serum alpha-2-macroglobulin associate with diabetes status and incident CVD in type 1 diabetes.

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-04 DOI: 10.1016/j.jlr.2025.100741

Baohai Shao, Janet K Snell-Bergeon, Ian H de Boer, W Sean Davidson, Karin E Bornfeldt, Jay W Heinecke

{"title":"Elevated levels of serum alpha-2-macroglobulin associate with diabetes status and incident CVD in type 1 diabetes.","authors":"Baohai Shao, Janet K Snell-Bergeon, Ian H de Boer, W Sean Davidson, Karin E Bornfeldt, Jay W Heinecke","doi":"10.1016/j.jlr.2025.100741","DOIUrl":"10.1016/j.jlr.2025.100741","url":null,"abstract":"Atherosclerotic CVD is a major cause of death in individuals with type 1 diabetes mellitus (T1DM). However, conventional risk factors do not fully account for the increased risk. This study aimed to investigate whether serum proteins associate with diabetes status and the occurrence of CVD in T1DM. We used isotope dilution-MS/MS to quantify 28 serum proteins in 228 subjects participating in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used linear regression to analyze the association between serum protein levels and T1DM status using 47 healthy controls and 134 T1DM patients without CVD and Cox proportional hazards regression to assess their prediction for incident CVD by a case-cohort study using a subcohort of 145 T1DM subjects and a total of 47 CVD events. Of the 28 serum proteins studied, five of them-alpha-2-macroglobulin (A2M), apolipoprotein A-IV, apolipoprotein L1, insulin-like growth factor 2, and phospholipid transfer protein-were significantly associated with T1DM status, with A2M being 1.6-fold higher in T1DM. After adjusting for potential confounders, A2M independently predicted incident CVD, with a mean hazard ratio of 3.3 and 95% CI of 1.8-6.1. In our study, A2M showed the largest increase in serum levels when comparing patients with T1DM to control subjects. A2M also predicted incident CVD, suggesting that it could serve as both a marker and possibly a mediator of atherosclerosis in T1DM. These findings emphasize the importance of specific serum proteins in assessing and managing CVD risk in T1DM.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100741"},"PeriodicalIF":5.0,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066124","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

Small molecule-driven LKB1 deacetylation is responsible for the inhibition of hepatic lipid response in NAFLD. 小分子驱动的LKB1去乙酰化是NAFLD中抑制肝脏脂质反应的原因。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-02 DOI: 10.1016/j.jlr.2024.100740

Weiwei Qin, Yu Ding, Wenhao Zhang, Lu Sun, Jianping Weng, Xueying Zheng, Sihui Luo

{"title":"Small molecule-driven LKB1 deacetylation is responsible for the inhibition of hepatic lipid response in NAFLD.","authors":"Weiwei Qin, Yu Ding, Wenhao Zhang, Lu Sun, Jianping Weng, Xueying Zheng, Sihui Luo","doi":"10.1016/j.jlr.2024.100740","DOIUrl":"10.1016/j.jlr.2024.100740","url":null,"abstract":"Nonalcoholic fatty liver disease (NAFLD) is a progressive condition characterized by ectopic fat accumulation in the liver, for which no FAD-approved drugs currently exist. Emerging evidence highlights the role of liver kinase B1 (LKB1), a key metabolic regulator, has been proposed in NAFLD, particularly in response to excessive nutrient levels. However, few agents have been identified that can prevent the progression of nonalcoholic steatohepatitis (NASH) by targeting LKB1 deacetylation. Through comprehensive screening of our in-house chemical library, we identified tranilast, a small molecule with remarkable inhibitory efficacy against lipid deposition induced by palmitic acid/oleic acid (PO). In this study, we investigated the novel biological function and mechanism of tranilast in regulating hepatic lipid response in NAFLD, focusing on its role in LKB1 deacetylation within hepatocytes. Our findings demonstrate that tranilast effectively reduced hepatic steatosis, inflammation, and fibrosis in NASH models induced by high-fat and high-cholesterol (HFHC) and methionine choline-deficient (MCD) diets. Mechanistic analysis using RNA sequencing revealed that tranilast mitigated hepatic lipid response by promoting LKB1 deacetylation and activating AMPK. Notably, in vivo experiments showed that the beneficial effects of tranilast in MCD diet-induced NASH model were reversed by the compound C (C-C), a known AMPK inhibitor, confirming that tranilast's effects on hepatic lipid response are mediated through the AMPK pathway. In summary, tranilast inhibits hepatic lipid response in NAFLD through LKB1 deacetylation, providing robust experimental evidence for the role of LKB1 in NAFLD. These findings position tranilast as a promising therapeutic candidate for the pharmacological management of metabolic diseases.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100740"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927374","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

Identification of plasma proteins binding oxidized phospholipids using pull-down proteomics and OxLDL masking assay. 利用下拉蛋白质组学和 OxLDL 掩蔽试验鉴定与氧化磷脂结合的血浆蛋白。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-11-19 DOI: 10.1016/j.jlr.2024.100704

Philipp Jokesch, Lisa Holzer, Lydia Jantscher, Sebastian Guttzeit, Rudolf Übelhart, Olga Oskolkova, Valery Bochkov, Bernd Gesslbauer

{"title":"Identification of plasma proteins binding oxidized phospholipids using pull-down proteomics and OxLDL masking assay.","authors":"Philipp Jokesch, Lisa Holzer, Lydia Jantscher, Sebastian Guttzeit, Rudolf Übelhart, Olga Oskolkova, Valery Bochkov, Bernd Gesslbauer","doi":"10.1016/j.jlr.2024.100704","DOIUrl":"10.1016/j.jlr.2024.100704","url":null,"abstract":"Oxidized phospholipids (OxPLs) are increasingly recognized as toxic and proinflammatory mediators, which raises interest in the mechanisms of their detoxification. Circulating OxPLs are bound and neutralized by plasma proteins, including both antibodies and non-immunoglobulin proteins. The latter group of proteins is essentially not investigated because only three OxPC-binding plasma proteins are currently known. The goal of this work was to characterize a broad spectrum of plasma proteins selectively binding OxPLs. Using pull-down-proteomic analysis, we found about 150 non-immunoglobulin proteins preferentially binding oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylcholine (OxPAPC) as compared to non-oxidized PAPC. To test if candidate proteins indeed can form a barrier isolating OxPLs from recognition by other proteins, we applied an immune masking assay. Oxidized LDL (OxLDL) immobilized in multiwell plates was used as a carrier of OxPLs, while mAbs recognizing OxPC or OxPE were used as \"detectors\" showing if OxPLs on the surface of OxLDL are physically accessible to external binding partners. Using an orthogonal combination of pull-down and masking assays we confirmed that previously described OxPL-binding proteins (non-fractionated IgM, CFH, and Apo-M) indeed can bind to and mask OxPC and OxPE on liposomes and OxLDL. Furthermore, we identified additional plasma proteins selectively binding and masking OxPC including Apo-D, Apo-H, pulmonary surfactant-associated protein B, and antithrombin-III. We hypothesize that in addition to circulating antibodies, multiple non-immunoglobulin plasma proteins can also bind OxPLs and modulate their recognition by innate and adaptive immunity.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100704"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment. 建立低DHA状态的新型斑马鱼模型，研究母体营养在神经发育中的作用。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1016/j.jlr.2024.100716

Katherine M Ranard, Bruce Appel

{"title":"Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.","authors":"Katherine M Ranard, Bruce Appel","doi":"10.1016/j.jlr.2024.100716","DOIUrl":"10.1016/j.jlr.2024.100716","url":null,"abstract":"Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR/Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with an abnormal eye phenotype and demonstrate that even morphologically normal siblings exhibit dysregulated vision and stress response gene pathways. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities, and provide insight into maternal nutritional strategies that optimize infant brain health.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100716"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glycosylation of ceramide synthase 6 is required for its activity. 神经酰胺合成酶6的糖基化是其活性所必需的。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-11-26 DOI: 10.1016/j.jlr.2024.100715

Alexandra J Straus, Grace Mavodza, Can E Senkal

{"title":"Glycosylation of ceramide synthase 6 is required for its activity.","authors":"Alexandra J Straus, Grace Mavodza, Can E Senkal","doi":"10.1016/j.jlr.2024.100715","DOIUrl":"10.1016/j.jlr.2024.100715","url":null,"abstract":"Sphingolipids play key roles in membrane structure and cellular signaling. Ceramide synthase (CerS)-generated ceramide is implicated in cellular stress responses and induction of apoptosis. Ceramide and other sphingolipids are linked to the induction of ER stress response pathways. However, the mechanisms by which ceramide modulates ER stress signaling are not well understood. Here, we show that the ER stress inducer brefeldin A (BFA) causes increased glycosylation of CerS6, and that treatment with BFA causes increased endogenous ceramide accumulation. To our surprise, we found that CerS6 activity was not affected by BFA-induced glycosylation. Instead, our data show that basal glycosylation of CerS6 at Asn18 is required for CerS6 activity. We used a robust HCT116 CRISPR-Cas9 CerS6 KO with reintroduction of either WT CerS6 or a mutant CerS6 with a point mutation at asparagine-18 to an alanine (N18A) which abrogated glycosylation at that residue. Our data show that cells stably expressing the N18A mutant CerS6 had significantly lower activity in vitro and in situ as compared to WT CerS6 expressing cells. Further, the defective CerS6 with N18A mutation also had defects in GSK3β, AKT, JNK, and STAT3 signaling. Despite being required for CerS6 activity, Asn18 glycosylation did not influence ER stress response pathways. Overall, our study provides vital insight into the regulation of CerS6 activity by posttranslational modification at Asn18 and identifies glycosylation of CerS6 to be important for ceramide generation and regulation of downstream cellular signaling pathways.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100715"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ki-67 and CDK1 control the dynamic association of nuclear lipids with mitotic chromosomes. Ki-67和CDK1控制核脂质与有丝分裂染色体的动态关联。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-12-18 DOI: 10.1016/j.jlr.2024.100731

Hsiao-Tang Hu, Ueh-Ting Tim Wang, Bi-Chang Chen, Yi-Ping Hsueh, Ting-Fang Wang

{"title":"Ki-67 and CDK1 control the dynamic association of nuclear lipids with mitotic chromosomes.","authors":"Hsiao-Tang Hu, Ueh-Ting Tim Wang, Bi-Chang Chen, Yi-Ping Hsueh, Ting-Fang Wang","doi":"10.1016/j.jlr.2024.100731","DOIUrl":"10.1016/j.jlr.2024.100731","url":null,"abstract":"Nuclear lipids play roles in regulatory processes, such as signaling, transcriptional regulation, and DNA repair. In this report, we demonstrate that nuclear lipids may contribute to Ki-67-regulated chromosome integrity during mitosis. In COS-7 cells, nuclear lipids are enriched at the perichromosomal layer and excluded from intrachromosomal regions during early mitosis but are then detected in intrachromosomal regions during late mitosis, as revealed by TT-ExM (expansion microscopy with trypsin digestion and tyramide signal amplification), an improved expansion microscopy technique that enables high-sensitivity and super-resolution imaging of proteins, lipids, and nuclear DNA. The nuclear nonhistone protein Ki-67 acts as a surfactant to form a repulsive molecular brush around fully condensed sister chromatids in early mitosis, preventing the diffusion or penetration of nuclear lipids into intrachromosomal regions. Ki-67 is phosphorylated during mitosis by cyclin-dependent kinase 1 (CDK1), the best-known master regulator of the cell cycle. Both Ki-67 knockdown and reduced Ki-67 phosphorylation by CDK1 inhibitors allow nuclear lipids to penetrate chromosomal regions. Thus, both Ki-67 protein level and phosphorylation status during mitosis appear to influence the perichromosomal distribution of nuclear lipids. Ki-67 knockdown and CDK1 inhibition also lead to uneven chromosome disjunction between daughter cells, highlighting the critical role of this regulatory mechanism in ensuring accurate chromosome segregation. Given that Ki-67 has been proposed to promote chromosome individualization and establish chromosome-cytoplasmic compartmentalization during open mitosis in vertebrates, our results reveal that nuclear lipid enrichment at the perichromosomal layer enhances the ability of Ki-67 to form a protective perichromosomal barrier (chromosome envelope), which is critical for correct chromosome segregation and maintenance of genome integrity during mitosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100731"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis. DFCP1 是饥饿驱动的 ATGL 介导的脂滴溶脂的调节器

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-11-19 DOI: 10.1016/j.jlr.2024.100700

Victoria A Ismail, Meg Schuetz, Zak N Baker, Jean A Castillo-Badillo, Teri V Naismith, David J Pagliarini, David J Kast

{"title":"DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis.","authors":"Victoria A Ismail, Meg Schuetz, Zak N Baker, Jean A Castillo-Badillo, Teri V Naismith, David J Pagliarini, David J Kast","doi":"10.1016/j.jlr.2024.100700","DOIUrl":"10.1016/j.jlr.2024.100700","url":null,"abstract":"Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100700"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HDL-free cholesterol influx into macrophages and transfer to LDL correlate with HDL-free cholesterol content. 高密度脂蛋白游离胆固醇流入巨噬细胞并转移至低密度脂蛋白与高密度脂蛋白游离胆固醇含量相关。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-11-19 DOI: 10.1016/j.jlr.2024.100707

Dedipya Yelamanchili, Baiba K Gillard, Antonio M Gotto, Miguel Caínzos Achirica, Khurram Nasir, Alan T Remaley, Corina Rosales, Henry J Pownall

{"title":"HDL-free cholesterol influx into macrophages and transfer to LDL correlate with HDL-free cholesterol content.","authors":"Dedipya Yelamanchili, Baiba K Gillard, Antonio M Gotto, Miguel Caínzos Achirica, Khurram Nasir, Alan T Remaley, Corina Rosales, Henry J Pownall","doi":"10.1016/j.jlr.2024.100707","DOIUrl":"10.1016/j.jlr.2024.100707","url":null,"abstract":"High-density lipoprotein (HDL)-free cholesterol (FC) transfers to other lipoproteins and cells, the former by a spontaneous mechanism and the latter by both spontaneous and receptor-mediated mechanisms. Macrophages are an important cell type in all stages of atherosclerotic cardiovascular disease (ASCVD), and the magnitude of FC efflux from macrophages to HDL, a metric of HDL function, inversely associated with several metrics of ASCVD. Very high plasma HDL concentrations are associated with increased all-cause and ASCVD mortality, suggesting that the reverse process, FC influx from HDL into macrophages, is atherogenic. We hypothesize that HDL-FC is a metric of dysfunctional HDL, and when combined with HDL particle number (HDL-P), is an ASCVD risk factor. The magnitude of FC influx from HDL to macrophages is expected to be a function of HDL-P and HDL-FC content. Here we show that plasma HDL-FC content varies 2-fold among normolipidemic human subjects and linearly correlates with low-density lipoprotein (LDL)-FC content. The influx of HDL-FC into macrophages and transfer to LDL increase linearly with HDL-FC. As expected, the influx of HDL-FC into macrophages and the transfer to LDL are positively correlated. These data support the hypothesis that high HDL FC content is a marker for dysfunctional HDL, resulting in greater influx into macrophages and greater HDL-FC transfer to LDL. HDL-FC transfer to LDL is a valid surrogate for influx into macrophages. This study of HDL composition and function of normolipidemic subjects provides the basis for further investigation and establishment of HDL-FC content as an ASCVD risk factor.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100707"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lysosphingolipids in ceramide-deficient skin lipid models. 神经酰胺缺乏皮肤脂质模型中的溶鞘磷脂。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-12-07 DOI: 10.1016/j.jlr.2024.100722

Georgios Paraskevopoulos, Lukáš Opálka, Andrej Kováčik, Anna Paraskevopoulou, Eleni Panoutsopoulou, Irene Sagrafena, Petra Pullmannová, Robert Čáp, Kateřina Vávrová

{"title":"Lysosphingolipids in ceramide-deficient skin lipid models.","authors":"Georgios Paraskevopoulos, Lukáš Opálka, Andrej Kováčik, Anna Paraskevopoulou, Eleni Panoutsopoulou, Irene Sagrafena, Petra Pullmannová, Robert Čáp, Kateřina Vávrová","doi":"10.1016/j.jlr.2024.100722","DOIUrl":"10.1016/j.jlr.2024.100722","url":null,"abstract":"Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with \"healthy\" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100722"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel mutation, Ile344Asn, in microsomal triglyceride transfer protein abolishes binding to protein disulfide isomerase. 微粒体甘油三酯转移蛋白中的一种新突变Ile344Asn消除了与蛋白质二硫异构酶的结合。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-12-12 DOI: 10.1016/j.jlr.2024.100725

Swati Valmiki, Cindy Bredefeld, M Mahmood Hussain

{"title":"A novel mutation, Ile344Asn, in microsomal triglyceride transfer protein abolishes binding to protein disulfide isomerase.","authors":"Swati Valmiki, Cindy Bredefeld, M Mahmood Hussain","doi":"10.1016/j.jlr.2024.100725","DOIUrl":"10.1016/j.jlr.2024.100725","url":null,"abstract":"Microsomal triglyceride transfer protein (MTP) plays crucial roles in the assembly and secretion of apolipoprotein B-containing lipoproteins and loss of function MTP variants are associated with abetalipoproteinemia, a disease characterized by the absence of these lipoproteins. MTP is a heterodimeric protein of two subunits, MTP and protein disulfide isomerase (PDI). In this study, we report a proband with abetalipoproteinemia who was monitored annually for 10 years in her third decade and had very low plasma lipids and undetectable apoB-containing lipoproteins. Genetic testing revealed biallelic variants in the MTTP gene. She has a well-documented nonsense mutation Gly865∗ that does not interact with the PDI subunit. She also has a novel missense MTP mutation, Ile344Asn. We show that this mutation abrogates lipid transfer activity in MTP and does not support apolipoprotein B secretion. This residue is present in the central α-helical domain of MTP and the substitution of Ile with Asn at this position disrupts interactions between MTP and PDI subunits. Ile344 is away from the known MTP:PDI interacting sites identified in the crystal structure of MTP suggesting that MTP:PDI interactions are more dynamic than previously envisioned. Identification of more missense mutations will enhance our understanding of the structure-function of MTP and the role of critical residues in these interactions between the two subunits. This knowledge may guide us in developing novel treatment modalities to reduce plasma lipids and atherosclerosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100725"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0