Journal of Lipid Research最新文献

{"title":"Hexokinase 2 promotes ISGylation of Acyl-CoA synthetase long-chain family member 4 in sepsis-induced microglia cells.","authors":"Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling","doi":"10.1016/j.jlr.2025.100776","DOIUrl":"10.1016/j.jlr.2025.100776","url":null,"abstract":"<p><p>Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100776"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630355","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":"Spatial characterization of RPE structure and lipids in the PEX1-p.Gly844Asp mouse model for Zellweger spectrum disorder.","authors":"Samy Omri, Catherine Argyriou, Rachel S Pryce, Erminia Di Pietro, Pierre Chaurand, Nancy Braverman","doi":"10.1016/j.jlr.2025.100771","DOIUrl":"10.1016/j.jlr.2025.100771","url":null,"abstract":"<p><p>Zellweger Spectrum Disorder (ZSD) is caused by defects in PEX genes, whose proteins are required for peroxisome assembly and function. Peroxisome dysfunction in ZSD causes multisystem effects, with progressive retinal degeneration (RD) among the most frequent clinical findings. However, much remains unknown about how peroxisome deficiency causes RD. To study RD pathophysiology in ZSD, we used the PEX1-p.Gly844Asp (G844D) mouse model, which represents the common human PEX1-p.Gly843Asp (G843D) variant. We previously reported diminished retinal function, diminished functional vision, and neural retina structural defects in this model. Here, we investigate the retinal pigment epithelium (RPE) phenotype, examining morphological, inflammatory, and lipid changes at 1, 3, and 6 months of age. We report that RPE cells exhibit evident degeneration by 3 months that worsens with time, starts in the dorsal pole, and is accompanied by subretinal inflammatory cell infiltration. We match these events with imaging mass spectrometry for regional analysis of lipids in the RPE. We identified 47 lipid alterations preceding structural changes, 9 of which localize to the dorsal pole. 29 of these persist to 3 months, with remodeling of the dorsal pole lipid signature. 13 new alterations occur concurrent with histological changes. Abnormalities in peroxisome-dependent lipids detected by LC/MS/MS are exacerbated over time. This study represents the first characterization of RPE in a ZSD model, and the first in situ lipid analysis in peroxisome-deficient tissue. Our findings uncover potential lipid drivers of RD progression in ZSD, and identify candidate biomarkers for retinopathy progression and response to therapy.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100771"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585987","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 reaction specificity of mammalian ALOX15B orthologs does not depend on the evolutionary ranking of the animals.","authors":"Eda Gündem, Sabine Stehling, Astrid Borchert, Hartmut Kuhn","doi":"10.1016/j.jlr.2025.100768","DOIUrl":"10.1016/j.jlr.2025.100768","url":null,"abstract":"<p><p>Arachidonic acid lipoxygenases (ALOXs) play important roles in cell differentiation and in the pathogenesis of cardiovascular, hyperproliferative, neurodegenerative, and metabolic diseases. The human genome involves six intact ALOX genes and knockout studies of the corresponding mouse orthologs indicated that the coding multiplicity of ALOX isoforms is not an indication for functional redundancy. Despite their evolutionary relatedness human and mouse ALOX15 and ALOX15B orthologs exhibit different catalytic properties. Human ALOX15 oxygenates arachidonic acid mainly to 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid but 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid is the dominant oxygenation product of mouse Alox15. This functional difference is the results of a targeted enzyme evolution but the driving forces for this process have not been well defined. For human and mouse ALOX15B orthologs similar functional differences have been reported but for the time being it was unclear whether these differences might also be a consequence of targeted enzyme evolution. To address this question, we systematically searched the public databases for ALOX15B genes, expressed selected enzymes, and characterized their functional properties. We found that functional ALOX15B genes frequently occur in Prototheria and Eutheria but orthologous genes are rare in Metatheria. The vast majority of mammalian ALOX15B orthologs constitute arachidonic acid 15-lipoxygenating enzymes and this property did not depend on the evolutionary ranking of the animals. Only several Muridae species including M. musculus, M. pahari, M. caroli, M. coucha, and A. niloticus express arachidonic acid 8-lipoxygenating ALOX15B orthologs. Consequently, the difference in the reaction specificity of mouse and human ALOX15B orthologs may not be considered a functional consequence of targeted enzyme evolution.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100768"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567403","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":"S-adenosylmethionine deficit disrupts very low-density lipoprotein metabolism promoting liver lipid accumulation in mice.","authors":"María R Luque-Urbano, David Fernández-Ramos, Fernando Lopitz-Otsoa, Virginia Gutiérrez de Juan, Maider Bizkarguenaga, Lia Castro-Espadas, Uxue Hermoso-Martínez, Lucía Barbier-Torres, Shelly C Lu, Oscar Millet, José M Mato","doi":"10.1016/j.jlr.2025.100794","DOIUrl":"10.1016/j.jlr.2025.100794","url":null,"abstract":"<p><p>Hepatic deletion of methionine adenosyltransferase-1a (Mat1a) in mice reduces S-adenosylmethionine (SAMe), a key methyl donor essential for many biological processes, which promotes the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperglycemia and reduced MAT1A expression, along with low SAMe levels, are common in MASLD patients. This study explores how Mat1a-knockout (KO) hepatocytes respond to prolonged high glucose conditions, focusing on glucose metabolism and lipid accumulation. Hepatocytes from methionine adenosyltransferase-1a-knockout (Mat1a-KO) mice were incubated in high glucose conditions overnight, allowing for analysis of key metabolic intermediates and gene expression related to glycolysis, gluconeogenesis, glyceroneogenesis, phospholipid synthesis, and very low density lipoprotein (VLDL) secretion. SAMe deficiency in Mat1a-KO hepatocytes led to reduced protein methyltransferase-1 activity, resulting in increased expression of glycolytic enzymes (glucokinase, phosphofructokinase, and pyruvate kinase) and decreased expression of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase). These alterations led to a reduction in dihydroxyacetone phosphate (DHAP), which subsequently inhibited mammalian target of rapamycin complex 1 (mTORC1) activity. This inhibition resulted in decreased phosphatidylcholine synthesis via the CDP-choline pathway and impaired VLDL secretion, ultimately causing lipid accumulation. Thus, under high glucose conditions, SAMe deficiency in hepatocytes depletes DHAP, inhibits mTORC1 activity, and promotes lipid buildup.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100794"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780307","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":"Potential causal evidence for an ApoB-independent and HDL-related risk profile associated with coronary artery disease.","authors":"Linjun Ao, Diana van Heemst, J Wouter Jukema, Patrick C N Rensen, Ko Willems van Dijk, Raymond Noordam","doi":"10.1016/j.jlr.2025.100778","DOIUrl":"10.1016/j.jlr.2025.100778","url":null,"abstract":"<p><p>Plasma ¹H-NMR metabolomic measures have yielded significant insight into the pathophysiology of cardiometabolic disease, but their inter-related nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated ¹H-NMR metabolomic profiles with coronary artery disease (CAD) and ischemic stroke (IS). Principal component (PC) analysis was performed on 168 ¹H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve uncorrelated PCs, which were used in Cox-proportional hazard models. For each outcome, two-sample Mendelian randomization analyses were then conducted based on three nonoverlapping databases, followed by a meta-analysis. The first six PCs collectively explaining 88% of the total variance were identified. For CAD, results from Cox and Mendelian randomization analyses were generally directionally consistent. The pooled odds ratios (95% CI) for CAD per one-SD increase in genetically influenced PC1 and PC3 (both characterized by distinct apolipoprotein B [ApoB]-associated lipoprotein profiles) were 1.04 (1.03, 1.05) and 0.94 (0.93, 0.96), respectively. Besides, the pooled odds ratio (95% CI) for CAD per one-SD increase in genetically influenced PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 (1.03, 1.07). For IS, increases of PC3 and PC5 (characterized by increased amino acids) were associated with a lower risk and a higher risk, respectively. This study confirms associations of ApoB-associated lipoprotein profiles with CAD and IS, and highlights the possible existence of an ApoB-independent lipoprotein profile, characterized by a distinctive HDL subparticle distribution, driving CAD.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100778"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634160","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":"Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function?","authors":"Graeme I Lancaster, Andrew J Murphy","doi":"10.1016/j.jlr.2025.100765","DOIUrl":"10.1016/j.jlr.2025.100765","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of cell death driven by the excessive peroxidation of poly-unsaturated fatty acids (PUFAs) within membrane phospholipids. Ferroptosis is a hallmark of many diseases and preventing or inducing ferroptosis has considerable therapeutic potential. Like other forms of cell death, the pathological importance and therapeutic potential of ferroptosis is well appreciated. However, while cell death modalities such as apoptosis and necroptosis have critical physiological roles, such as in development and tissue homeostasis, whether ferroptosis has important physiological roles is largely unknown. In this regard, key questions for field are as follows: Is ferroptosis used for physiological processes? Are certain cell-types purposely adapted to be either resistant or sensitive to ferroptosis to be able to function optimally? Do physiological perturbations such as aging and diet impact ferroptosis susceptibility? Herein, we have reviewed emerging evidence that supports the idea that being able to selectively and controllably induce or resist ferroptosis is essential for development and cell function. While several factors regulate ferroptosis, it appears that the ability of cells and tissues to control their lipid composition, specifically the abundance of phospholipids containing PUFAs, is crucial for cells to be able to either resist or be sensitized to ferroptosis. Finally, aging and diets enriched in specific PUFAs lead to an increase in cellular PUFA levels which may sensitize cells to ferroptosis. Therefore, changes in dietary PUFAs or againg may impact the pathogenesis of diseases where ferroptosis is involved.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100765"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531002","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":"Foamy monocytes and atherogenesis in mice with combined hyperlipidemia and effects of antisense knockdown of apoCIII.","authors":"Xueying Peng, Zeqin Lian, Veronica O'Brien, Jing Xiao, Benjamin A Litchfield, Xiao-Yuan Dai Perrard, Lu Xu, Jing Ni, Aparna Mukherjee, Timothy Simmons, Henry Dong, Adam E Mullick, Rosanne Crooke, Henry J Pownall, Scott I Simon, Christie M Ballantyne, Huaizhu Wu","doi":"10.1016/j.jlr.2025.100763","DOIUrl":"10.1016/j.jlr.2025.100763","url":null,"abstract":"<p><p>Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr^-/- mice (Ldlr^-/-ApoCIIItg) fed Western high-fat diet (WD). Tissue culture with THP-1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins on monocytes. Ldlr^-/-ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr^-/- mice, Ldlr^-/-ApoCIIItg mice fed WD had early and persistent increases in lipid accumulation within monocytes and enhanced atherosclerosis. Ldlr^-/-ApoCIIItg mice versus Ldlr^-/- mice had higher levels of CD11c, CD36, and cytokines in foamy monocytes, with increases in foamy monocyte adhesion to vascular cell adhesion molecule-1 and oxidized LDL uptake. Monocytes took up TG-rich lipoprotein in vivo and in vitro and changed phenotypes. Foamy monocytes infiltrated into atherosclerotic lesions, and specific and sustained depletion of CD11c⁺ (foamy) monocytes profoundly reduced atherosclerosis in Ldlr^-/-ApoCIIItg mice on WD. Treatment with apoCIII ASO lowered plasma TG and cholesterol levels, improved foamy monocyte phenotypes, and reduced atherosclerosis in Ldlr^-/-ApoCIIItg mice. In conclusion, HTG in combined hyperlipidemia accelerates atherosclerosis, in part, by increasing foamy monocyte formation and infiltration into atherosclerotic plaques. Treatment with apoCIII ASO is a potential new therapy for improving monocyte phenotypes and reducing atherosclerosis in combined hyperlipidemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100763"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483398","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":"Impact of genetic markers related to hyper-HDL cholesterol on the prevalence of myocardial infarction: a KoGES study.","authors":"Sung-Bum Lee, Kyung-Won Hong, Byoungjin Park, Dong-Hyuk Jung","doi":"10.1016/j.jlr.2025.100777","DOIUrl":"10.1016/j.jlr.2025.100777","url":null,"abstract":"<p><p>Recent studies have shown that hyper-high-density lipoprotein cholesterol (HDL-C) is associated with cardiovascular disease risk and all-cause mortality, a phenomenon known as the HDL-C paradox. Several genes have been reported to show relationships between increased HDL-C and myocardial infarction (MI) risk. We investigated the genetic predisposition of lipid metabolism influencing MI. The study dataset was from the Korean Genome and Epidemiology cohort obtained from the National Biobank of Korea, with an initial population of 68,806 individuals. We categorized samples based on HDL-C levels into hypo-HDL-C (n = 25,884), normal-HDL-C (n = 41,117), and hyper-HDL-C groups (n = 1,805). We conducted genome-wide association studies for each group and the total sample. Significant associations were defined using genome-wide significant level and suggestive level. The lead SNP of each locus was selected for further interpretation. This analysis included 2,014 (2.6%) MI patients. Using multivariable logistic regression, we evaluated the association of 7,877 SNPs in nine loci. We identified six SNPs significantly related to both hypo- and hyper-HDL groups, one SNP associated with hyper-HDL, and six SNPs associated with hypo-HDL group. Additionally, we found three SNPs associated with MI prevalence in the hyper-HDL group, including one significant SNP and two suggestive SNPs. Contrary to the traditional view of HDL-C as protective, this study identified genetic variants that increase MI risk by more than six-fold. These SNPs could play a role as important markers for detecting MI in hyper-HDL cholesterol group.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100777"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634074","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":"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":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin regulates lymphatic endothelial integrity via palmitoylation.","authors":"Silvia Gonzalez-Nieves, Xiaochao Wei, Simon Guignard, Thi Nguyen, Jay McQuillan, Qiang Zhang, Jinsong Zhang, Reagan M McGuffee, David A Ford, Clay F Semenkovich, Vincenza Cifarelli","doi":"10.1016/j.jlr.2025.100775","DOIUrl":"10.1016/j.jlr.2025.100775","url":null,"abstract":"<p><p>Lipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and vessel maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. Thus, understanding how lipid metabolism affects LECs is critical for uncovering the mechanisms underlying lymphatic dysfunction. Protein palmitoylation, a lipid-based post-translational modification, has emerged as a critical regulator of protein function, stability, and interaction networks. Insulin, a master regulator of systemic lipid metabolism, also regulates protein palmitoylation. However, the role of insulin-driven palmitoylation in LEC biology remains unexplored. To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin-regulated targets, and determined the role of palmitoylation in LEC barrier function. In unstimulated conditions, palmitoylation occurred primarily on proteins involved in vesicular and membrane trafficking, and in translation initiation. Insulin treatment, instead, enriched palmitoylation of proteins involved in LEC integrity, namely junctional proteins such as claudin 5, along with small GTPases and ubiquitination enzymes. We also investigated the role of the long-chain fatty acid transporter CD36, a major mediator of palmitate uptake into cells, in regulating optimal lymphatic protein palmitoylation. CD36 silencing in LECs increased by 2-fold palmitoylation of proteins involved in inflammation and immune cell activation. Overall, our findings provide novel insights into the intricate relationship between lipid modification and LEC function, suggesting that insulin and palmitoylation play a critical role in lymphatic endothelial function.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100775"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624970","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}