Journal of Lipid Research最新文献

{"title":"Impaired ApoB secretion triggers enhanced secretion of ApoE to maintain triglyceride homeostasis in hepatoma cells.","authors":"Kotomi Shinozaki, Tomoko Honda, Kenzaburo Yamaji, Emi Nishijima, Ikuyo Ichi, Daisuke Yamane","doi":"10.1016/j.jlr.2025.100795","DOIUrl":"10.1016/j.jlr.2025.100795","url":null,"abstract":"<p><p>Apolipoprotein B (ApoB) is essential for the assembly and secretion of triglyceride (TG)-rich VLDL particles, and its dysfunction is linked to metabolic disorders, including dyslipidemia and liver steatosis. However, less attention has been paid to whether and how other apolipoproteins play redundant or compensatory roles when the ApoB function is compromised. Here, we investigated the effects of microsomal triglyceride transfer protein (MTP), which mediates lipidation of nascent ApoB, on ApoE function. We observed a paradoxical increase in ApoE secretion resulting from increased expression in MTP inhibitor (MTPi)-treated human hepatoma cells. This phenotype was recapitulated in APOB-knockout cells and was associated with impaired ApoB secretion. While MTP-dependent transfer of neutral lipids is dispensable for ApoE secretion, TG biosynthesis, redundantly catalyzed by DGAT1 and DGAT2, is required for efficient ApoE secretion in hepatoma cells. ApoE colocalizes with lipid droplets near the Golgi apparatus and mediates TG export in an ApoB-independent fashion. We found that simultaneous inhibition of both ApoE and ApoB, but not inhibition of either alone, led to TG accumulation in hepatoma cells, indicating that both proteins function redundantly to control TG content. Validation studies in primary human hepatocytes (PHHs) demonstrated DGAT2-dependent secretion of ApoE. While MTPi treatment did not elevate ApoE secretion, it induced increased sialylation of ApoE in the supernatants of PHHs. These results show that enhanced ApoE secretion compensates for the impaired ApoB function to maintain the lipid homeostasis, providing an alternative route to modulate lipid turnover in hepatoma cells.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100795"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780304","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":"MUSTN1 and FABP3 interact to regulate adipogenesis and lipid deposition.","authors":"Yu Fu, Xin Hao, Jingru Nie, Hongliang Zhang, Peng Shang, Bo Zhang, Hao Zhang","doi":"10.1016/j.jlr.2025.100804","DOIUrl":"10.1016/j.jlr.2025.100804","url":null,"abstract":"<p><p>Lipid deposition is related to agricultural animal production and human health, and elucidating its molecular regulatory mechanisms is a topic of interest and a challenge in current scientific research. Musculoskeletal embryonic nuclear protein 1 (MUSTN1) regulates growth and development, including muscle tissue; however, its role in fat deposition remains unknown. Thus, our objective was to determine this role. Our new findings were as follows: MUSTN1 was highly expressed in the fat tissue of pigs with strong adipose deposition capacity; functionally, MUSTN1 promoted the proliferation and adipogenic differentiation of porcine and mouse preadipocytes. MUSTN1 knockout mice were protected against HFD-induced obesity, hepatic steatosis, and insulin resistance; and fatty acid binding protein 3 was identified as an interacting protein of MUSTN1, which facilitated preadipocyte proliferation and differentiation by activating the phosphatidylinositol 3 kinase/AKT signaling pathways. This study reveals a positive regulator for fat development, which suggests a novel approach for studying obesity and animal genetic improvement through the modulation of MUSTN1 expression.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 5","pages":"100804"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008519","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":"PPARɑ variant V227A reduces plasma triglycerides through enhanced lipoprotein lipolysis.","authors":"Lauren F Uchiyama, Gabriel P M Ordonez, Khoi T Pham, John P Kennelly, Maykel López Rodríguez, Lany Tran, Peter Tontonoz, Alexander Nguyen","doi":"10.1016/j.jlr.2025.100806","DOIUrl":"10.1016/j.jlr.2025.100806","url":null,"abstract":"<p><p>Human single nucleotide variants in peroxisome proliferator-activated receptor-ɑ (PPARɑ) have been associated with beneficial metabolic phenotypes, yet their specific effects on metabolic gene expression are not well defined. Here, we developed a mouse model of a human PPARɑ variant encoding a substitution of valine for alanine at position 227 (V227A) to explore the role of this variant on systemic metabolism. Substitution with this variant in mice reduced plasma triglycerides, without altering body mass or liver lipid accumulation, consistent with phenotypes observed in human cohorts. Gene expression analysis revealed that the V227A variant enhances Ppara target gene expression in mouse liver, consistent with the effects of synthetic PPARɑ agonist treatment. Notably, V227A increased hepatic expression of Lpl, the predominant enzyme responsible for circulating triglyceride hydrolysis. Further characterization revealed that heart tissue from variant mice exhibited increased Lpl expression and triglyceride hydrolysis activity, suggesting that V227A enhances cardiac triglyceride clearance. These findings validate human observational studies and clarify the physiological impact of the V227A PPARɑ variant on plasma triglycerides.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100806"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029420","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":"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":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147223/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetyl-11-keto-β-boswellic acid alleviates hepatic metabolic dysfunction by inhibiting MGLL activity.","authors":"Kai Luan, Yuhong Fan, Qin Yang, Hailong Yang, Zelin Zhou, Ju Huang, Zhigang She, Toujun Zou, Hui Xiong, Zhinan Mei","doi":"10.1016/j.jlr.2025.100812","DOIUrl":"10.1016/j.jlr.2025.100812","url":null,"abstract":"<p><p>Metabolic abnormalities have emerged as a central pathogenesis in various metabolic diseases, particularly nonalcoholic fatty liver disease (NAFLD) and its associated complications of obesity and insulin resistance. Despite this, effective pharmaceutical treatments for NAFLD-related metabolic disorders remain limited. In this study, we identified acetyl-11-keto-beta-boswellic acid (AKBA), a natural compound isolated from the gum resin of Boswellia carterii, showing robust capacity against NAFLD as well as its related body weight gain and insulin resistance. Our findings demonstrate that the beneficial effects of AKBA on metabolic disorders are largely dependent on its direct interaction with monoacylglycerol lipase (MGLL) in hepatocytes. In vivo experiments using a high-fat and high-cholesterol (HFHC) diet-induced NAFLD mouse model revealed that AKBA effectively mitigated both the progression of NAFLD and associated metabolic dysfunctions. Proteomic and RNA sequencing analyses further elucidated that AKBA attenuates key pathways related to lipid accumulation, inflammation, and fibrosis. Mechanistically, AKBA was found to directly target MGLL in hepatocytes, inhibiting its activity in hydrolyzing monoacylglycerols. Structural analyses revealed that AKBA binds specifically to the GLU60, MET64, THR279, and PHE283 residues of MGLL. Importantly, AKBA showed no additional therapeutic effect in MGLL-deficient models, underscoring the crucial role of MGLL in mediating AKBA's therapeutic action. In conclusion, our study identifies AKBA as a novel and potent MGLL inhibitor and suggests that it holds promise as a therapeutic candidate for NAFLD and related metabolic diseases. This research highlights the potential of natural compounds in the development of targeted treatments for metabolic disorders.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 5","pages":"100812"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986191","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":"Modulation of endogenous plasmalogens by genetic ablation of lysoplasmalogenase (Tmem86b) in mice.","authors":"Sudip Paul, Pooranee Morgan, Gerard Pernes, Yvette Schooneveldt, Thy Duong, Natalie A Mellett, Kevin Huynh, Andrew J Murphy, Graeme I Lancaster, Peter J Meikle","doi":"10.1016/j.jlr.2025.100808","DOIUrl":"10.1016/j.jlr.2025.100808","url":null,"abstract":"<p><p>Plasmalogens are a distinct subclass of glycerophospholipids that exhibit unique structural features, notably possessing a vinyl ether linkage at the sn1 position of the glycerol backbone. These specialized lipids play crucial roles in various biological functions. Although the biosynthetic pathway of plasmalogens has been well-characterized, their catabolism remains less studied. In this study, we investigated the impact of global and tissue-specific loss-of-function of a plasmalogen catabolizing enzyme, lysoplasmalogenase (TMEM86B), on circulatory and tissue lipidomes. We generated both global and hepatocyte-specific Tmem86b knockout mice using cre-loxP technology. Mice with homozygous global inactivation of Tmem86b (Tmem86b KO mice) were viable and did not display any marked phenotypic abnormalities. Tmem86b KO mice demonstrated significantly elevated levels of the plasmalogens, alkenylphosphatidylethanolamine (PE(P)), and alkenylphosphatidylcholine (PC(P)), as well as lysoplasmalogens, in the plasma, liver, and natural killer cells compared to their wild-type counterparts. The endogenous alkenyl chain composition of plasmalogens remained unaltered in Tmem86b KO mice. Consistent with the global knockout findings, hepatocyte-specific Tmem86b knockout mice also exhibited increased plasmalogen levels in the plasma and liver compared to their floxed control counterparts. Overall, our findings shed light on the role of Tmem86b in plasmalogen catabolism, demonstrating how its ablation leads to elevated plasmalogen levels in select tissues and cells. This study enhances our understanding of the regulatory mechanisms governing plasmalogen metabolism and highlights the potential of targeting Tmem86b to therapeutically raise plasmalogen levels.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100808"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969952","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":"Phosphatidylserine-decorated delivery platform helps alleviate acute lung injury via potentiating macrophage targeting.","authors":"Yue Li, Hu Li, Zhiwei Hu, Yayue Zhang, Xuran Ding, Xinjie Huang, Yabing Hua, Lin Sun, Ye Li, Ziming Zhao, Yuan He","doi":"10.1016/j.jlr.2025.100799","DOIUrl":"10.1016/j.jlr.2025.100799","url":null,"abstract":"<p><p>Acute lung injury (ALI) is a life-threatening inflammatory disease with high morbidity and mortality. It is urgent to develop more effective therapeutic strategies against ALI. Phosphatidylserine (PtdSer) expressed on the surface of apoptotic cells not only allows for macrophage binding and recognition but also drives anti-inflammatory signaling within the macrophage. In this study, we designed an apoptotic cell-mimicry nanoparticle by decorating synthetic PtdSer on the outer face of nanoparticles. The results indicated that PtdSer-decorated poly(lactic-co-glycolic acid) nanoparticles (PSNPs) showed anti-inflammatory properties and increased macrophage phagocytosis in relative to the nondecorated poly(lactic-co-glycolic acid nanoparticles. Dexamethasone-loaded PSNPs exhibited superior anti-inflammatory activity on macrophages in vitro. In vivo studies also showed that PtdSer decoration increased the accumulation of nanoparticles in lung macrophages after pulmonary administration. Accumulation of dexamethasone-loaded PSNPs in lung macrophages effectively reduced inflammation in inflamed lungs and further alleviated ALI syndromes. In conclusion, PtdSer decoration not only endows the anti-inflammatory function to nanocarriers but also potentiates its macrophage targeting in the inflamed microenvironment, which offers an ideal drug delivery platform for ALI therapy.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 5","pages":"100799"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996594","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":"The one-key-to-two-doors role of lipidomics: plasma lipidome, cardiovascular risk and statin usage.","authors":"Anatol Kontush","doi":"10.1016/j.jlr.2025.100802","DOIUrl":"10.1016/j.jlr.2025.100802","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"66 5","pages":"100802"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013861","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":"Clinical lipidomics reveals high individuality and sex specificity of circulatory lipid signatures: a prospective healthy population study.","authors":"Jessica Medina, Nicolas Goss, Gonçalo Dos Santos Correia, Rebecca Borreggine, Tony Teav, Zoltan Kutalik, Pedro Marques Vidal, Hector Gallart-Ayala, Julijana Ivanisevic","doi":"10.1016/j.jlr.2025.100780","DOIUrl":"10.1016/j.jlr.2025.100780","url":null,"abstract":"<p><p>Lipid metabolism and circulatory lipid levels are tightly associated with the (cardio)metabolic health. Consequently, MS-based lipidomics has emerged as a powerful phenotyping tool in epidemiological, human population, and in clinical intervention studies. However, ensuring high-throughput and reproducible measurement of a wide panel of circulatory lipid species in large-scale studies poses a significant challenge. Here, we applied a recently developed quantitative LC-MS/MS lipidomics approach to a subset of 1,086 fasted plasma samples belonging to apparently healthy participants from prospective Lausanne population study. This high-coverage and high-throughput hydrophilic interaction liquid chromatography-based methodology allowed for the robust measurement of 782 circulatory lipid species spanning 22 lipid classes and six orders of magnitude-wide concentration range. This was achieved by combining semiautomated sample preparation using a stable isotope dilution approach and the alternate analysis of National Institute of Standards and Technology plasma reference material, as a quality control. Based on National Institute of Standards and Technology quality control analysis, median between-batch reproducibility was 8.5%, over the course of analysis of 13 independent batches comprising 1,086 samples collected from 364 individuals at three time points. Importantly, the biological variability, per lipid species, was significantly higher than the batch-to-batch analytical variability. Furthermore, the significantly lower between-subject (than within-subject) variability and unsupervised sample clustering demonstrated the high individuality and sex specificity of circulatory lipidome. The most prominent sex differences were reported for sphingomyelins and ether-linked phospholipids present in significantly higher concentrations in female plasma. The high individuality and sex specificity of circulatory lipidome constitute important pre-requisites for the application of lipidomics in next-generation metabolic health monitoring.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100780"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670111","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":"High-density lipoproteins and COVID-19: preparing the next pandemic.","authors":"Marie Laurine Apalama, Floran Begue, Sébastien Tanaka, Maxime Cournot, David Couret, Olivier Meilhac, Mohammad Ryadh Pokeerbux","doi":"10.1016/j.jlr.2025.100779","DOIUrl":"10.1016/j.jlr.2025.100779","url":null,"abstract":"<p><p>High-density lipoproteins (HDLs) are heterogeneous particles with pleiotropic functions including anti-inflammatory and anti-infectious effects. In clinical studies, lower HDL-associated cholesterol (HDL-C) concentration has been associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and mortality. A reduction in the number of HDL particles, particularly small ones has been observed with alterations in their protein and lipid composition impairing their functions. These observations have supported HDL supplementation with promising results in small preliminary studies. This review summarizes available evidence to better understand the two-way interaction between HDLs and Coronavirus disease 2019 (COVID-19) and guide future HDL-based therapies for preparing for the next pandemic.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100779"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639486","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}