Journal of Lipid Research最新文献

{"title":"Efficacy of a novel PCSK9 inhibitory peptide alone and with evinacumab in a mouse model of atherosclerosis.","authors":"José A Inia, Anita van Nieuwkoop-van Straalen, J Wouter Jukema, Bidda Rolin, Ellen Marie Staarup, Christina K Mogensen, Hans M G Princen, Anita M van den Hoek","doi":"10.1016/j.jlr.2025.100753","DOIUrl":"10.1016/j.jlr.2025.100753","url":null,"abstract":"<p><p>Atherosclerosis is the major cause of cardiovascular disease. This study evaluated the effect of lipid lowering using a novel peptide inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and a monoclonal antibody against angiopoietin-like 3 (evinacumab), either alone or in combination in APOE∗3-Leiden.CETP mice fed a Western diet. Effects on body weight, plasma lipids, atherosclerotic lesion size, severity, composition, and morphology were assessed. Treatment with PCSK9 inhibitory peptide significantly decreased both cholesterol and triglycerides (-69% and -68%, respectively). Similar reductions were seen in evinacumab-treated mice (-44% and -55%, respectively). The combination of evinacumab and PCSK9 inhibitory peptide lowered these levels to a larger extent than evinacumab alone (cholesterol: -74%; triglycerides: -81%). Reductions occurred in non-HDL-C without changes in HDL-C. Atherosclerotic lesion size was significantly reduced in all treatment groups compared to vehicle controls (evinacumab: -72%; PCSK9 inhibitory peptide: -97%; combination: -98%). Similarly, all interventions improved atherosclerotic lesion severity, with more undiseased segments and fewer severe lesions. Evaluation of the composition of severe atherosclerotic plaques revealed significant improvement in lesion stability in mice treated with both evinacumab and PCSK9 inhibitory peptide, attributable to decreased macrophage content and increased collagen content. Additionally, evaluation of lipid concentrations in cynomolgus monkeys revealed the beneficial effects of the PCSK9 inhibitory peptide on total cholesterol and LDL-C levels. Treatment with a novel PCSK9 inhibitory peptide alone or with evinacumab shows great potential to reduce and stabilize atherosclerotic lesions.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100753"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255873","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":"Comparison of the capillary and venous blood plasma lipidomes: validation of self-collected blood for plasma lipidomics.","authors":"Ahsan Hameed, Mario G Ferruzzi, Colin D Kay, D Keith Williams, Elaheh Rahbar, Andrew J Morris","doi":"10.1016/j.jlr.2025.100755","DOIUrl":"10.1016/j.jlr.2025.100755","url":null,"abstract":"<p><p>Venipuncture of the upper extremities is commonly used to collect blood for plasma lipidomics. However, self-administered blood collection devices such as the Tasso+™ system for capillary blood sampling and plasma separation are convenient and enable frequent sampling without a clinical blood draw. The purpose of this study is to validate Tasso+ sampling for plasma lipidomics by comparing the venous blood and Tasso+-sampled capillary blood plasma lipidomes. Lipids are proven or putative biomarkers of human health and disease and indicators of nutritional and toxicological status. Because exchange of blood components including lipids occurs in capillaries, the capillary and venous blood lipidomes might be different, which could confound use of Tasso+-sampled blood as a surrogate for venous blood plasma. Here we compared the lipidomes of Tasso+-drawn capillary blood plasma and venous blood plasma in 10 male subjects using high-resolution mass spectrometry-based lipidomics. While there was substantial interindividual variability between lipidomes, comprehensive statistical approaches with cross-validation and multiple testing adjustments showed no difference (adjusted P-value > 0.05) in lipid composition of the paired blood samples. A linear regression model with Spearman correlation analysis also showed a significant-to-near-perfect level (r = 0.95-0.99) of concordance between the samples. Aside from monoacylglycerols and cardiolipins, every class of lipid was strongly correlated (r = 0.9-0.99) between paired venous and capillary blood plasma. In summary, the capillary and venous blood plasma lipidomes are essentially identical making self-administered collection of capillary blood a viable approach for clinical blood plasma lipidomics.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100755"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425600","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":"Distinct pathways for the absorption and metabolism of β-carotene and zeaxanthin in the mouse intestine.","authors":"Sepalika Bandara, Aicha Saadane, Tong Shen, Daryna Yakovleva, Rakhee Banerjee, Yanqi Zhang, J Mark Brown, Johannes von Lintig","doi":"10.1016/j.jlr.2025.100758","DOIUrl":"10.1016/j.jlr.2025.100758","url":null,"abstract":"<p><p>Carotenoids, essential nutrients for eye health, are absorbed in the intestine to support vitamin A homeostasis and provide cellular protection. This process involves the lipid transporters scavenger receptor class B type 1 (SR-B1, encoded by Scarb1 gene) and Niemann-Pick C1-Like 1 (NPC1L1), which load these dietary lipids into the plasma membrane of intestinal enterocytes. However, the precise contribution of these transporters to carotenoid absorption, the putative involvement of Aster proteins in their downstream movement, and the interactions with their metabolizing enzymes, β-carotene oxygenase 1 (BCO1) and β-carotene oxygenase 2 (BCO2), remain incompletely understood. Here, we investigated carotenoid metabolism in the mouse intestine using pharmacological and genetic approaches. We observed that ezetimibe, an NPC1L1 inhibitor, reduced zeaxanthin but did not affect β-carotene absorption. Aster-C, highly expressed in enterocytes, bound zeaxanthin in biochemical assays. In mice, Aster-C deficiency led to upregulation of Gramd1b (Aster-B) expression and increased zeaxanthin bioavailability. We further showed that BCO1 directly interacted with membranes to extract β-carotene for retinoid production, indicating that vitamin A production is Aster protein-independent. This observation is consistent with the finding that the intestine-specific transcription factor ISX, the master regulator of vitamin A production, controlled Scarb1 and Bco1 expression but had no effect on Gramd1a, b, or c, encoding Aster proteins in intestinal enterocytes. Together, our study revealed distinct pathways for β-carotene and zeaxanthin absorption and metabolism, offering new insights into carotenoid bioavailability and potential strategies to optimize dietary carotenoid intake for improved eye health.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100758"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458300","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":"Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression.","authors":"Genta Kakiyama, Nanah Bai-Kamara, Daniel Rodriguez-Agudo, Hajime Takei, Kei Minowa, Michael Fuchs, Sudha Biddinger, Jolene J Windle, Mark A Subler, Tsuyoshi Murai, Mitsuyoshi Suzuki, Hiroshi Nittono, Arun Sanyal, William M Pandak","doi":"10.1016/j.jlr.2025.100757","DOIUrl":"10.1016/j.jlr.2025.100757","url":null,"abstract":"<p><p>Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1^hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their WT counterparts, WD-fed CYP7B1^hep.tg mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1^hep.tg mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation, and immune system including retinol metabolism, arachidonic acid metabolism, and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1^hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1^hep.tg mouse liver accumulated 26HC and 25HC in response to WD. These data strongly suggested that these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a \"proof-of-concept\" that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100757"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425601","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":"ABCA1-mediated nascent HDL formation is precisely regulated by the plasma membrane cholesterol.","authors":"Fumihiko Ogasawara, Kazumitsu Ueda","doi":"10.1016/j.jlr.2025.100762","DOIUrl":"10.1016/j.jlr.2025.100762","url":null,"abstract":"<p><p>Intracellular cholesterol transport is essential for maintaining cellular cholesterol homeostasis. ATP-binding cassette A1 (ABCA1) continuously moves cholesterol from the inner leaflet to the outer leaflet of the plasma membrane (PM) to maintain low inner leaflet cholesterol levels. When PM inner leaflet cholesterol levels exceed ER cholesterol levels, which are maintained at approximately 5 mol% by the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP), Aster-A/GramD1a transports the excess cholesterol to the ER. Furthermore, ABCA1 removes excess PM cholesterol by promoting its efflux as nascent high-density lipoprotein (HDL) particles. Thus, cellular cholesterol homeostasis is maintained by the coordinated action of SCAP-SREBP, Aster-A/GramD1a, and ABCA1. While the regulation of SCAP-SREBP and Aster-A/GramD1a is well-understood, the mechanism governing ABCA1 activity remains less understood. In this study, we investigated the impact of PM cholesterol levels on ABCA1-mediated cholesterol and phosphatidylcholine (PC) efflux. Cells were treated with various concentrations of methyl-β-cyclodextrin (MβCD) or MβCD-cholesterol for 30 min to modulate PM cholesterol levels. We found that the initial velocities of both cholesterol and PC efflux were dependent solely on PM cholesterol levels, despite both being substrates for ABCA1. Intriguingly, when PM cholesterol levels dropped below 70% of the level observed in cells cultured in the presence of 10% FBS, both cholesterol and PC efflux ceased, even in the presence of abundant PC in the PM. Our findings suggest that ABCA1-mediated nascent HDL formation is precisely regulated to maintain optimal PM cholesterol levels.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100762"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468318","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":"Multilayer regulation of postprandial triglyceride metabolism in response to acute cold exposure.","authors":"Yiliang Zhang, Shengyang Zhou, Runming Zhao, Chunyu Xiong, Yingzhen Huang, Minzhu Zhang, Yan Wang","doi":"10.1016/j.jlr.2025.100751","DOIUrl":"10.1016/j.jlr.2025.100751","url":null,"abstract":"<p><p>Triglyceride-rich lipoproteins carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multilayered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100751"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074795","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":"Divergent effects of monomethyl branched-chain fatty acids on energy metabolism and insulin signaling in human myotubes.","authors":"Parmeshwar Bajirao Katare, Ragna H Tingstad, Sivar T Beajani, Jørgen Pasjkurov Indseth, Vibeke H Telle-Hansen, Mari C W Myhrstad, Arild C Rustan, Lars Eide, Oliwia Witczak, Vigdis Aas","doi":"10.1016/j.jlr.2025.100764","DOIUrl":"10.1016/j.jlr.2025.100764","url":null,"abstract":"<p><p>Branched-chain fatty acids (BCFAs) are predominantly saturated fatty acids with one or more methyl branches on the carbon chain, typically found in dairy products and measured in micromolar concentrations in human plasma. The biological function of BCFAs in humans remains ill-defined, but a relationship between circulating BCFAs and cardiometabolic health has been suggested. The objective of this study was to evaluate the impact of BCFAs on energy metabolism in human myotubes. The results revealed distinct effects of BCFAs. 12-Methyltetradecanoic acid (12-MTD) increased glucose uptake and glycogen synthesis, while 13-methyltetradecanoic acid (13-MTD), 14-methylhexadecanoic acid (14-MHD), and 15-methylhexadecanoic acid (15-MHD) increased oleic acid uptake and 13-MTD and 15-MHD oleic acid oxidation, indicating a more general stimulatory effect on fatty acid than glucose metabolism. Interestingly, the same BCFAs, 13-MTD, 14-MHD, and 15-MHD, appeared to reduce insulin-stimulated glycogen synthesis. Insulin-stimulated phosphorylation of IRS1 was not apparent after exposure to 12-MTD, 13-MTD, and 15-MHD, whereas insulin-stimulated phosphorylation of Akt was unchanged by BCFAs. Incorporation of [¹⁴C]leucine into lipids was affected, as 13-MTD increased the total lipid content, and 12-MTD altered the distribution of lipid classes. Metabolic flux analysis indicated that 14-MHD stimulated extracellular acidification. The effects of BCFAs might involve increased mRNA expression of pyruvate dehydrogenase kinase 4. In conclusion, the study demonstrates that different BCFAs have distinct effects on energy metabolism in myotubes, 12-MTD mainly affect glucose metabolism, while 13-MTD, 14-MHD, and 15-MHD modulated oleic acid metabolism. These data suggest that some BCFAs might have therapeutic applications by improving energy metabolism.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100764"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515888","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":"Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.","authors":"Beibei Chen, Ruixia Bao, Jujie Pan, Zicheng Zhu, Qian Chen, Dan Wang, Yuzheng Wu, Haiyang Yu, Yi Zhang, Tao Wang","doi":"10.1016/j.jlr.2025.100746","DOIUrl":"10.1016/j.jlr.2025.100746","url":null,"abstract":"<p><p>Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites upregulate 3-hydroxy-3-methylglutaryl-CoA. Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of 3-hydroxy-3-methylglutaryl-CoA by activating adenosine A2A receptor via the Srebp-2/Creb axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting adenosine A2A receptor. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100746"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028947","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":"Physiological accumulation of lipid droplets in the newborn liver during breastfeeding is driven by TLR4 ligands.","authors":"Wanderson Ferreira da Silva Júnior, Karen Marques de Oliveira Costa, Hortência Maciel Castro Oliveira, Maísa Mota Antunes, Kassiana Mafra, Brenda Naemi Nakagaki, Pedro Sérgio Corradi da Silva, Júlia Duarte Megale, Sarah Campos de Sales, Douglas Carvalho Caixeta, Mário Machado Martins, Robinson Sabino-Silva, Cristina Maria Pinto de Paula, Luiz Ricardo Goulart, Rafael Machado Rezende, Gustavo Batista Menezes","doi":"10.1016/j.jlr.2025.100744","DOIUrl":"10.1016/j.jlr.2025.100744","url":null,"abstract":"<p><p>The liver plays a central role in fat storage, but little is known about physiological fat accumulation during early development. Here we investigated a transient surge in hepatic lipid droplets observed in newborn mice immediately after birth. We developed a novel model to quantify liver fat content without tissue processing. Using high-resolution microscopy assessed the spatial distribution of lipid droplets within hepatocytes. Lugol's iodine staining determined the timing weaning period, and milk deprivation experiments investigated the relationship between milk intake and fat accumulation. Lipidomic analysis revealed changes in the metabolic profile of the developing liver. Finally, we investigated the role of Toll-like receptor 4 (TLR4) signaling in fat storage using knockout mice and cell-specific deletion strategies. Newborn mice displayed a dramatic accumulation of hepatic lipid droplets within the first 12 h after birth, persisting for the initial two weeks of life. This pattern coincided with exclusive milk feeding and completely abated by the third week, aligning with weaning. Importantly, the observed fat accumulation shared characteristics with established models of pathological steatosis, suggesting potential biological relevance. Lipid droplets were primarily localized within the cytoplasm of hepatocytes. Milk deprivation experiments demonstrated that milk intake is the primary driver of this transient fat accumulation. Lipidomic analysis revealed significant changes in the metabolic profile of newborn livers compared to adults. Interestingly, several highly abundant lipids in newborns were identified as putative ligands for TLR4. Subsequent studies using TLR4-deficient mice and cell-specific deletion revealed that TLR4 signaling, particularly within hepatocytes, plays a critical role in driving fat storage within the newborn liver. Additionally, a potential collaboration between metabolic and immune systems was suggested by the observed effects of myeloid cell-specific TLR4 ablation. This study demonstrates a unique phenomenon of transient hepatic fat accumulation in newborn mice driven by milk intake and potentially regulated by TLR4 signaling, particularly within hepatocytes.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100744"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006809","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":"Contribution of individual phospholipase A₂ enzymes to the cleavage of oxidized phospholipids in human blood plasma.","authors":"Philipp Jokesch, Olga Oskolkova, Maria Fedorova, Bernd Gesslbauer, Valery Bochkov","doi":"10.1016/j.jlr.2025.100742","DOIUrl":"10.1016/j.jlr.2025.100742","url":null,"abstract":"<p><p>Phospholipids containing oxidized esterified PUFA residues (OxPLs) are increasingly recognized for multiple biological activities and causative involvement in disease pathogenesis. Pharmacokinetics of these compounds in blood plasma is essentially not studied. Human plasma contains both genuine phospholipases A₂ [platelet activating factor acetyl hydrolase (PAF-AH) (also called Lp-PLA₂) and secretory phospholipase A2] and multifunctional enzymes capable of removing sn-2 residues in native and oxidized PLs (lecithin-cholesterol acyltransferase, peroxiredoxin-6). The goal of this study was to compare relative activities of different PLA₂ enzymes by analyzing cleavage of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylcholine (OxPAPC) and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylethanolamine (OxPAPE) by diluted plasma in the presence of enzyme inhibitors. We have found that human plasma demonstrated high total PLA₂ activity against oxidized PCs and PEs. PAF-AH/Lp-PLA₂ played a dominant role in LysoPC and LysoPE production as compared to other enzymes. Molecular species of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylcholine and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylethanolamine could be divided into three groups according to their degradation rate and sensitivity to PAF-AH/Lp-PLA₂ inhibitor darapladib. Oxidatively truncated species were most rapidly metabolized in the presence of plasma; this process was strongly inhibited by darapladib. The rate of degradation of full-length OxPLs depended on the degree of oxygenation. Species containing 1 to 3 oxygen atoms were relatively stable to degradation in plasma, while OxPLs containing > 3 extra oxygens were degraded but at significantly slower rate than truncated species. In contrast to truncated species, degradation of full-length OxPLs with > 3 extra oxygens were only minimally inhibited by darapladib. These data provide further insights into the mechanisms regulating circulating levels of OxPLs and lipid mediators generated by PLA₂ cleavage of OxPLs, namely oxylipins and LysoPC.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100742"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950238","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}