Journal of Lipid Research最新文献

{"title":"Mechanisms and functional implications of ZDHHC5 in cellular physiology and disease.","authors":"Huicong Liu, Shuo Wen, Chang Xu, Xiaohong Kang, Eryan Kong","doi":"10.1016/j.jlr.2025.100793","DOIUrl":"10.1016/j.jlr.2025.100793","url":null,"abstract":"<p><p>Post-translational lipid modification by palmitoylation is a reversible process crucial for maintaining cellular functionality. The palmitoyl acyltransferase zinc finger Asp-His-His-Cys motif-containing 5 (ZDHHC5) has garnered significant attention due to its roles in neurodegenerative diseases, oncogenesis, and cardiac function. ZDHHC5 recognizes substrates through diverse mechanisms and its activity is regulated by multiple factors. Highly expressed in the brain, liver, and heart, ZDHHC5 exerts regulatory functions in various cellular processes through self-regulation and substrate palmitoylation. This review summarizes ZDHHC5's regulatory roles in the nervous system, lipid metabolism and oncogenesis, highlighting its potential as a therapeutic target for neurological, lipid metabolic diseases, and cancer due to its involvement in diverse cellular processes and disease-associated dysfunctions.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100793"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780305","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}

{"title":"Functional characterization of TMEM86A and TMEM86B mutants by a novel lysoplasmalogenase assay.","authors":"Denise Kummer, Ilaria Dorigatti, Theresia Dunzendorfer-Matt, Georg Golderer, Ernst R Werner, Katrin Watschinger","doi":"10.1016/j.jlr.2025.100766","DOIUrl":"10.1016/j.jlr.2025.100766","url":null,"abstract":"<p><p>Plasmalogens are an abundant class of glycero-phospholipids with a characteristic 1-O-alk-1'-enyl double bond. While their synthesis has been extensively investigated, their degradation remains understudied. Plasmalogen deficiencies are associated with severe disorders in humans and interfering with their degradation would be a treatment option, but it remains out of reach due to limited knowledge. The plasmalogen double bond is degraded either directly by a plasmalogenase or by conversion to the 2' lyso forms by phospholipase and subsequent cleavage by lysoplasmalogenase (E.C. 3.3.2.2). Two lysoplasmalogenases are known so far, TMEM86A and TMEM86B. While TMEM86B has been expressed in bacteria, purified, and shown to encode lysoplasmalogenase activity by a coupled optical assay, the closely related protein TMEM86A has not yet been purified, but its activity was shown indirectly by a lipidomics approach. Here, we present a novel assay for lysoplasmalogenase activity based on incubation with lysoplasmenylethanolamine or lysoplasmenylcholine, derivatization of the aldehyde product with dansylhydrazine, and hydrazone quantification by reversed-phase HPLC with fluorescence detection. The method was sensitive enough to robustly detect lysoplasmalogenase activity in human embryonic kidney cells following transient expression of TMEM86A or TMEM86B and also suitable for the determination of lysoplasmalogenase activity in mouse tissues where highest activities were found in liver and duodenum. We introduced point mutations at positions proposed to be catalytically relevant and provided experimental evidence that all but one affected lysoplasmalogenase activity. Our novel assay allows direct and fast measurement of lysoplasmalogenase activity, thereby providing a tool to advance research in the field of plasmalogen degradation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100766"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11994398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537263","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}

{"title":"Purifying selection of the lysosomal enzymes arylsulfatase A and beta-galactocerebrosidase and their evolutionary impact on myelin integrity.","authors":"Matthew A Luetzen, Richik Chakraborty, Oscar Andrés Moreno-Ramos, Olga Yaneth Echeverri-Peña, Yoko Satta, Adriana M Montaño","doi":"10.1016/j.jlr.2025.100769","DOIUrl":"10.1016/j.jlr.2025.100769","url":null,"abstract":"<p><p>The myelin is responsible for providing stability to the axons of the nerve cells, but above all, to improve transmission speed of the nerve impulse in vertebrates. Over 70% of the myelin sheath is composed of lipids and the remaining portion by approximately 2,000 proteins. The myelin sheath has been constantly evolving, and it is known that unusually high concentrations of galactosylceramide (GalCer) and its sulfated form play a major role in the biophysical properties of the myelin. To gain insights of the evolutionary role of GalCer, we have studied two lysosomal enzymes involved in GalCer degradation, arylsulfatase A (ARSA) and galactocerebrosidase (GALC). Deficiency of ARSA or GALC causes demyelinating disorders. We conducted phylogenetic analyses of 105 ARSA and 110 GALC orthologs representing more than 600 million years ago of evolution. We examined i) low values of the ratio of nonsynonymous to synonymous nucleotide-substitution rates (dN/dS) indicating purifying selection and ii) negative selection of amino acids located in the active site preventing pathogenic mutations. Gene structure analyses showed evidence of rearrangement with gain and loss of exons while there were conserved regions mainly located around the active site. We also found a limited number of sites under positive selection pressure that do not cause alterations to the overall protein structure. Our results indicate that ARSA and GALC have been highly conserved during the evolutionary process to maintain the metabolism of GalCer, which is essential for the integrity of the white matter in vertebrate species.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100769"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585979","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}

{"title":"Phosphatidylcholine synthesis and remodeling in brain endothelial cells.","authors":"Mohamed H Yaghmour, Theja Sajeevan, Christoph Thiele, Lars Kuerschner","doi":"10.1016/j.jlr.2025.100773","DOIUrl":"10.1016/j.jlr.2025.100773","url":null,"abstract":"<p><p>Mammalian cells synthesize hundreds of different variants of their prominent membrane lipid phosphatidylcholine (PC), all differing in the side chain composition. This batch is constantly remodeled by the Lands cycle, a metabolic pathway replacing one chain at a time. Using the alkyne lipid lyso-phosphatidylpropargylcholine (LpPC), a precursor and intermediate in PC synthesis and remodeling, we study both processes in brain endothelial bEND3 cells. A novel method for multiplexed sample analysis by mass spectrometry is developed that offers high throughput and molecular species resolution of the propargyl-labeled PC lipids. Their time-resolved profiles and kinetic parameters of metabolism demonstrate the plasticity of the PC pool and the acute handling of lipid influx in endothelial cells differs from that in hepatocytes. Side chain remodeling as a form of lipid cycling adapts the PC pool to the cell's need and maintains lipid homeostasis. We estimate that endothelial cells possess the theoretical capacity to remodel up to 99% of their PC pool within 3.5 h using the Lands cycle. However, PC species are not subjected stochastically to this remodeling pathway as different species containing duplets of saturated, omega-3, and omega-6 side chains show different decay kinetics. Our findings emphasize the essential function of Lands cycling for monitoring and adapting the side chain composition of PC in endothelial cells.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100773"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615679","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}

{"title":"Altered liver lipidome markedly overlaps with human plasma lipids at diabetes risk and reveals adipose-liver interaction.","authors":"Ratika Sehgal, Markus Jähnert, Michail Lazaratos, Thilo Speckmann, Fabian Schumacher, Burkhard Kleuser, Meriem Ouni, Wenke Jonas, Annette Schürmann","doi":"10.1016/j.jlr.2025.100767","DOIUrl":"10.1016/j.jlr.2025.100767","url":null,"abstract":"<p><p>Present study explores the role of liver lipidome in driving T2D-associated metabolic changes. Elevated liver triacylglycerols, reduced PUFAs, and 86 differentially abundant lipid species were identified in diabetes-prone mice. Of these altered lipid species, 82 markedly overlap with human plasma lipids associated with T2D/CVD risk. Pathway enrichment highlighted sphingolipid metabolism, however, only five of all genes involved in the pathway were differentially expressed in the liver. Interestingly, overlap with adipose tissue transcriptome was much higher (57 genes), pointing toward an active adipose-liver interaction. Next, the integration of liver lipidome and transcriptome identified strongly correlated lipid-gene networks highlighting ceramide [Cer(22:0)], dihydroceramide(24:1), and triacylglycerol(58:6) playing a central role in transcriptional regulation. Putative molecular targets of Cer(22:0) were altered (Cyp3a44, Tgf-β1) in primary mouse hepatocytes treated with Cer(22:0). Early alteration of liver lipidome markedly depends on adipose tissue expression pattern and provides substantial evidence linking early liver lipidome alterations and risk of T2D.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100767"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567401","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}

{"title":"Cardiomyopathy in a c.1528G>C Hadha mouse is associated with cardiac tissue lipotoxicity and altered cardiolipin species.","authors":"Chibuike Eke, Shannon Babcock, Garen Gaston, Gabriela Elizondo, Hak Chung, Ayah Asal, Kathryn C Chatfield, Genevieve C Sparagna, Andrea E DeBarber, William Packwood, Jonathan R Lindner, Melanie B Gillingham","doi":"10.1016/j.jlr.2025.100792","DOIUrl":"10.1016/j.jlr.2025.100792","url":null,"abstract":"<p><p>Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a metabolic disorder caused by the loss of LCHAD enzymatic activity in the α-subunit of the trifunctional protein (TFPα), leading to impaired fatty acid oxidation (FAO). Patients with LCHADD often develop dilated cardiomyopathy. A previously unrecognized enzymatic function of TFPα as monolysocardiolipin acyltransferase (MLCL-AT) has been implicated in cardiolipin remodeling, crucial for mitochondrial cristae integrity. However, it remains unclear whether the common pathogenic variant c.1528G>C in HADHA impairs MLCL-AT activity in TFPα. In this study, we investigated whether cardiac cardiolipin profiles are altered in LCHADD and explored potential pathophysiological mechanisms, including heart lipid accumulation, changes in the cardiolipin synthesis pathway, and mitochondrial dynamics, utilizing a murine model of LCHADD carrying c.1528G>C variant that mimics the cardiomyopathy observed in humans. LCHADD mice developed eccentric hypertrophic cardiomyopathy from 3- to 12 months of age. 12-month-old LCHADD hearts exhibited altered cardiolipin profiles and increased oxidized cardiolipin. LCHADD hearts had higher lipid content, and the shift in fatty acid profile mirrored the shift in cardiolipin profile compared to wild-type controls, suggesting altered cardiolipin composition in LCHADD may be a reflection of accumulated lipids caused by lower FAO. No differential expression of cardiolipin synthesis and remodeling pathway enzymes was observed, suggesting minimal impact of the c.1528G>C variant on cardiolipin remodeling pathway. LCHADD hearts showed an altered ratio of OPA1 isoforms, and mitochondria with swelling and disorganized cristae were present. These findings suggest that altered fatty acid, cardiolipin profiles, and mitochondrial dynamics may contribute to LCHADD cardiomyopathy, warranting further studies.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100792"},"PeriodicalIF":5.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753094","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}

{"title":"Isomerization of bis(monoacylglycero)phosphate by acyl migration.","authors":"Akira Abe, Vania Hinkovska-Galcheva, Rakesh Verma, James A Shayman","doi":"10.1016/j.jlr.2025.100789","DOIUrl":"10.1016/j.jlr.2025.100789","url":null,"abstract":"<p><p>Bis(monoacylglycero)phosphates (BMPs) are biologically functional acidic lipids present in late endosomes and lysosomes. We recently reported that lysosomal phospholipase A2 (LPLA2, PLA2G15), the lysosomal enzyme mediating BMP catabolism, degrades BMP isomers with distinct substrate specificity. Specifically, sn-(3-oleoyl-2-hydroxy)-glycerol-1-phospho-sn-1'-(3'-oleoyl-2'-hydroxy)-glycerol (S,S-(3,3'-diC_18:1)-BMP) is a significantly better substrate for LPLA2 than S,S-(2,2'-diC_18:1)-BMP. S,S-(2,2'-diC_18:1)-BMP is generally considered the only biologically relevant BMP isomer. We investigated the isomerization of S,S-(2,2'-diC_18:1)-BMP to (S,S-(3,3'-diC_18:1)-BMP) in vitro and in cells. Thin-layer chromatography was used to distinguish S,S-(3,3'-diC_18:1)-BMP from S,S-(2,2'-diC_18:1)-BMP. S,S-(2,2'-diC_18:1)-BMP/1,2-di-O-(9Z-octadecenyl)-sn-glycero-3-phosphocholine liposomes were incubated at varying pH in the presence or absence of test substances. First, we studied bovine serum albumin, which is known to promote isomerization of 1-acyl-2-lysophosphatidylcholine. The formation of S,S-(3,3'-diC_18:1)-BMP in the presence of albumin increased in a time-dependent and albumin concentration-dependent manner under neutral conditions and was dependent on pH and the molar ratio of S,S-(2,2'-diC_18:1)-BMP in liposomes. Treatment of isomeric products generated during isomerization reaction with sn-1,3-specific lipase produced both oleic acid but also lyso-phosphatidylglycerol, indicating that the conversion of S,S-(2,2'-diC_18:1)-BMP to S,S-(3,3'-diC_18:1)-BMP is preceded via S,S-(2,3'-diC_18:1)-BMP. S,S-(3,3'-diC_18:1)-BMP formed was preferentially degraded by LPLA2 over the S,S-(2,2'-diC_18:1)-BMP. Proteins such as HSP70 and human serum albumin and metal ions such as Fe³⁺ and Zn²⁺ acted as cofactors promoting the isomerization of S,S-(2,2'-diC_18:1)-BMP under neutral conditions. At baseline, RAW 264.7 cells showed nonnegligible amounts of sn-1,3-specific lipase-sensitive BMPs. However, lipase-sensitive BMPs were increased by exposure to chloroquine or NH₄Cl, suggesting that cells undergo S,S-(2,2'-diacyl)-BMP isomerization upon alkalinization of intracellular acidic compartments.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100789"},"PeriodicalIF":5.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753129","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}

{"title":"Elevated high-density lipoprotein triglycerides increase atherosclerotic risk.","authors":"Weifang Liu, Shaoze Chen, Chengzhang Yang, Fang Lei, Xuewei Huang, Xingyuan Zhang, Tao Sun, Lijin Lin, Chuansen Wang, Yuanyuan Cao, Zhi-Gang She, Xuan Xiao, Hongliang Li","doi":"10.1016/j.jlr.2025.100791","DOIUrl":"10.1016/j.jlr.2025.100791","url":null,"abstract":"<p><p>The relationship between high-density lipoprotein (HDL) and atherosclerotic risk remains incompletely elucidated, potentially due to the inherent heterogeneity of HDL particles. Hypertriglyceridemia is associated with alterations in HDL composition. This study investigated the impact of elevated triglycerides (TG) on HDL and its association with coronary artery disease (CAD) risk using a large prospective cohort study and Mendelian randomization (MR). We found that elevated TG was associated with reduced HDL particle size, decreased concentrations of HDL components, and increased triglycerides in HDL (HDL-TG) (all P for trend < 0.001). The protective effects of HDL particle concentration and HDL cholesterol on CAD are attenuated with increasing serum TG levels. An independent and positive association between HDL-TG levels and incident CAD events (hazard ratio [HR] per 1 standard deviation increase: 1.066, 95% CI: 1.052-1.080, P < 0.001) was confirmed even after adjustment for established cardiovascular disease risk factors. MR analyses supported a causal role for HDL-TG in CAD development (inverse-variance weighted [IVW] method: odds ratios [ORs] of 1.120 (95% CI: 1.053-1.192, P < 0.001) and 1.141 (95% CI: 1.032-1.263, P = 0.010) for dataset groups 1 and 2, respectively). Drug-target MR analyses suggested a potential association between omega-3 fatty acids (OM3-FA) and lower HDL-TG levels, with LPL and DGAT2 as key pharmacological targets. Our findings suggest that elevated TG contributes to adverse alterations in HDL, elevating CAD risk. HDL-TG is an independent positive risk factor for CAD and a potential causal contributor to CAD development. OM3-FA supplementation may offer a therapeutic strategy for mitigating the CAD risk associated with elevated HDL-TG.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100791"},"PeriodicalIF":5.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753101","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}

{"title":"Associations between plasma 24(S)-hydroxycholesterol and neuropsychological profile in fragile X syndrome.","authors":"Asma Laroui, Daniela Rojas, Sophie Bouhour, Mélodie Proteau-Lemieux, Luc Galarneau, Sérine Benachenhou, Armita Abolghasemi, Rosalie Plantefeve, Pierre-Luc Mallet, François Corbin, Jean-François Lepage, Artuela Çaku","doi":"10.1016/j.jlr.2025.100787","DOIUrl":"10.1016/j.jlr.2025.100787","url":null,"abstract":"<p><p>Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 gene, characterized by low plasma cholesterol levels. Considering the essential role of brain cholesterol in signaling and synaptogenesis, it is important to screen for brain cholesterol abnormalities in FXS and explore their link with neuropsychological profiles. Brain cholesterol is synthesized in situ, and the excess is primarily converted to 24(S)-hydroxycholesterol (24(S)-OHC). 27-hydroxycholesterol (27-OHC) is the major cholesterol oxidation metabolite that crosses the blood-brain barrier from peripheral circulation into the brain. Plasma levels of 24(S)-OHC and 27-OHC were quantified in FXS and control individuals. The FXS group underwent transcranial magnetic stimulation to evaluate corticospinal excitability and inhibition. The clinical profile was assessed using questionnaires evaluating specific symptoms related to autism, aberrant behaviors, and anxiety. Study results show a significant decrease in plasma levels of 24(S)-OHC in FXS as compared to controls (78.48 nM ± 20.90 vs. 99.53 nM ± 32.30; P = 0.006). Moreover, a negative correlation was observed between plasma levels of 24(S)-OHC and motor evoked potential (r_s = -0.57; P = 0.05) in FXS. Similarly, a negative correlation was also found between plasma levels of 24(S)-OHC and the total score of the Social Communication Questionnaire (r_s = -0.72; P = 0.002) and the Anxiety Depression and Mood Scale (r_s = -0.61; P = 0.02). The 24(S)-OHC is associated with specific neurophysiological and behavioral characteristics in individuals with FXS. Larger studies are warranted to confirm the potential of 24(S)-OHC as a reliable biomarker for FXS.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100787"},"PeriodicalIF":5.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743020","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}

{"title":"Lecithin:cholesterol acyltransferase binds a discontinuous binding site on adjacent apolipoprotein A-I belts in HDL.","authors":"Bethany Coleman, Shimpi Bedi, John H Hill, Jamie Morris, Kelly A Manthei, Rachel C Hart, Yi He, Amy S Shah, W Gray Jerome, Tomas Vaisar, Karin E Bornfeldt, Hyun Song, Jere P Segrest, Jay W Heinecke, Stephen G Aller, John J G Tesmer, W Sean Davidson","doi":"10.1016/j.jlr.2025.100786","DOIUrl":"10.1016/j.jlr.2025.100786","url":null,"abstract":"<p><p>Lecithin:cholesterol acyltransferase (LCAT) is a high-density lipoprotein (HDL) modifying protein that profoundly affects the composition and function of HDL subspecies. The cholesterol esterification activity of LCAT is dramatically increased by apolipoprotein A-I (APOA1) on HDL, but the mechanism remains unclear. Using site-directed mutagenesis, cross-linking, mass spectrometry, electron microscopy, protein engineering, and molecular docking, we identified two LCAT binding sites formed by helices 4 and 6 from two antiparallel APOA1 molecules in HDL. Although the reciprocating APOA1 \"belts\" form two ostensibly symmetrical binding locations, LCAT can adopt distinct orientations at each site, as shown by our 9.8 Å cryoEM envelope. In one case, LCAT membrane binding domains align with the APOA1 belts and, in the other, the HDL phospholipids. By introducing disulfide bonds between the APOA1 helical domains, we demonstrated that LCAT does not require helical separation during its reaction cycle. This indicates that LCAT, anchored to APOA1 belts, accesses substrates and deposits products through interactions with the planar lipid surface. This model of the LCAT/APOA1 interaction provides insights into how LCAT and possibly other HDL-modifying factors engage the APOA1 scaffold, offering potential strategies to enhance LCAT activity in individuals with genetic defects.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100786"},"PeriodicalIF":5.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730392","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}