Journal of Lipid Research最新文献_第6页

A fluorescence lifetime-based novel method for accurate lipid quantification of BODIPY vital-stained C. elegans. 一种基于荧光寿命的新方法，用于准确定量 BODIPY 活力保持的秀丽隐杆线虫的脂质。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-19 DOI: 10.1016/j.jlr.2024.100646

Chen Xu, Jintao Luo, Yong Yu

{"title":"A fluorescence lifetime-based novel method for accurate lipid quantification of BODIPY vital-stained C. elegans.","authors":"Chen Xu, Jintao Luo, Yong Yu","doi":"10.1016/j.jlr.2024.100646","DOIUrl":"10.1016/j.jlr.2024.100646","url":null,"abstract":"Lipid droplets (LDs) are organelles associated with lipid storage and energy metabolism, thus, their morphology and quantity are of significant research interest. While commercially available BODIPY dye effectively labels LDs in various cell types, it also labels lysosome-related organelles (LROs) in C. elegans, leading to non-specific LD quantification. Here, we report that the fluorescent signals of BODIPY exhibit distinct fluorescence lifetime patterns for LROs and LDs, which can be captured, visualized, and filtered by fluorescence lifetime imaging microscopy. Furthermore, we proposed and validated a method based on fluorescence lifetime that can improve the accuracy of fat storage quantification in BODIPY vital-staining worms, which holds broad applications, including rapid and accurate LD quantification in forward genetic screening. Additionally, our method enables observing dynamic LD-LRO interactions in living worms, a unique capability of BODIPY vital staining. Our findings highlight distinct BODIPY fluorescence lifetime characteristics of LDs and LROs, providing a valuable tool for future research on LDs, LROs, or their interactions.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100646"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic siRNA targeting PLIN2 ameliorates steatosis, inflammation, and fibrosis in steatotic liver disease models. 靶向 PLIN2 的 siRNA 可改善脂肪肝模型中的脂肪变性、炎症和纤维化。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-08-24 DOI: 10.1016/j.jlr.2024.100635

Yao Wang, Jiaxin Zhou, Qi Yang, Xinmeng Li, Yifu Qiu, Yansong Zhang, Min Liu, Alan Jian Zhu

{"title":"Therapeutic siRNA targeting PLIN2 ameliorates steatosis, inflammation, and fibrosis in steatotic liver disease models.","authors":"Yao Wang, Jiaxin Zhou, Qi Yang, Xinmeng Li, Yifu Qiu, Yansong Zhang, Min Liu, Alan Jian Zhu","doi":"10.1016/j.jlr.2024.100635","DOIUrl":"10.1016/j.jlr.2024.100635","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. If left untreated, MASLD can progress from simple hepatic steatosis to metabolic dysfunction-associated steatohepatitis, which is characterized by inflammation and fibrosis. Current treatment options for MASLD remain limited, leaving substantial unmet medical needs for innovative therapeutic approaches. Here, we show that PLIN2, a lipid droplet protein inhibiting hepatic lipolysis, serves as a promising therapeutic target for MASLD. Hepatic PLIN2 levels were markedly elevated in multiple MASLD mouse models induced by diverse nutritional and genetic factors. The liver-specific deletion of Plin2 exhibited significant anti-MASLD effects in these models. To translate this discovery into a therapeutic application, we developed a GalNAc-siRNA conjugate with enhanced stabilization chemistry and validated its potent and sustained efficacy in suppressing Plin2 expression in mouse livers. This siRNA therapeutic, named GalNAc-siPlin2, was shown to be biosafe in mice. Treatment with GalNAc-siPlin2 for 6-8 weeks led to a decrease in hepatic triglyceride levels by approximately 60% in high-fat diet- and obesity-induced MASLD mouse models, accompanied with increased hepatic secretion of VLDL-triglyceride and enhanced thermogenesis in brown adipose tissues. Eight-week treatment with GalNAc-siPlin2 significantly improved hepatic steatosis, inflammation, and fibrosis in high-fat/high fructose-induced metabolic dysfunction-associated steatohepatitis models compared to control group. As a proof of concept, we developed a GalNAc-siRNA therapeutic targeting human PLIN2, which effectively suppressed hepatic PLIN2 expression and ameliorated MASLD in humanized PLIN2 knockin mice. Together, our results highlight the potential of GalNAc-siPLIN2 as a candidate MASLD therapeutic for clinical trials.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100635"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11440260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel eicosanoid signature in plasma provides diagnostic for metabolic dysfunction-associated steatotic liver disease. 血浆中的新型类二十碳烷特征可诊断代谢功能障碍相关性脂肪肝。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-18 DOI: 10.1016/j.jlr.2024.100647

Oswald Quehenberger, Aaron M Armando, Tiffany H Cedeno, Rohit Loomba, Arun J Sanyal, Edward A Dennis

{"title":"Novel eicosanoid signature in plasma provides diagnostic for metabolic dysfunction-associated steatotic liver disease.","authors":"Oswald Quehenberger, Aaron M Armando, Tiffany H Cedeno, Rohit Loomba, Arun J Sanyal, Edward A Dennis","doi":"10.1016/j.jlr.2024.100647","DOIUrl":"10.1016/j.jlr.2024.100647","url":null,"abstract":"There is a clinical need for a simple test implementable at the primary point of care to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) in the population. Blood plasma samples from adult patients with varying phenotypes of MASLD were used to identify a minimal set of lipid analytes reflective of underlying histologically confirmed MASLD. Samples were obtained from the NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database prospective cohort study (MASLD group; N = 301). Samples of control subjects were obtained from cohort studies at the University of California San Diego (control group; N = 48). Plasma samples were utilized for targeted quantitation of circulating eicosanoids, related bioactive metabolites, and polyunsaturated fatty acids by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) lipidomics analysis. Bioinformatic approaches were used to discover a panel of bioactive lipids that can be used as a diagnostic tool to identify MASLD. The final panel of fifteen lipid metabolites consists of 12 eicosanoid metabolites and 3 free fatty acids that were identified to be predictive for MASLD by multivariate area under the receiver operating characteristics curve (AUROC) analysis. The panel was highly predictive for MASLD with an AUROC of 0.999 (95% CI = 0.986-1.0) with only one control misclassified. A validation study confirmed the resulting MASLD LIPIDOMICS SCORE, which may require a larger-scale prospective study to optimize. This predictive model should guide the development of a non-invasive \"point-of-care\" test to identify MASLD patients requiring further evaluation for the presence of metabolic dysfunction-associated steatohepatitis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100647"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Specific approaches and limitations in (multi)-omic Mendelian randomization. 多）原子孟德尔随机化的具体方法和局限性。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-08-13 DOI: 10.1016/j.jlr.2024.100619

Arjen J Cupido, Mingqi Zhou, Aldons J Lusis, Marcus Seldin

引用次数: 0

A high-cholesterol zebrafish diet promotes hypercholesterolemia and fasting-associated liver steatosis. 高胆固醇斑马鱼饮食可促进高胆固醇血症和空腹相关性肝脏脂肪变性。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-08-31 DOI: 10.1016/j.jlr.2024.100637

Yang Jin, Darby Kozan, Eric D Young, Monica R Hensley, Meng-Chieh Shen, Jia Wen, Tabea Moll, Jennifer L Anderson, Hannah Kozan, John F Rawls, Steven A Farber

{"title":"A high-cholesterol zebrafish diet promotes hypercholesterolemia and fasting-associated liver steatosis.","authors":"Yang Jin, Darby Kozan, Eric D Young, Monica R Hensley, Meng-Chieh Shen, Jia Wen, Tabea Moll, Jennifer L Anderson, Hannah Kozan, John F Rawls, Steven A Farber","doi":"10.1016/j.jlr.2024.100637","DOIUrl":"10.1016/j.jlr.2024.100637","url":null,"abstract":"Zebrafish are an ideal model organism to study lipid metabolism and to elucidate the molecular underpinnings of human lipid-associated disorders. Unlike murine models, to which various standardized high lipid diets such as a high-cholesterol diet (HCD) are available, there has yet to be a uniformly adopted zebrafish HCD protocol. In this study, we have developed an improved HCD protocol and thoroughly tested its impact on zebrafish lipid deposition and lipoprotein regulation in a dose- and time-dependent manner. The diet stability, reproducibility, and fish palatability were also validated. Fish fed HCD developed hypercholesterolemia as indicated by significantly elevated ApoB-containing lipoproteins (ApoB-LPs) and increased plasma levels of cholesterol and cholesterol esters. Feeding of the HCD to larvae for 8 days produced hepatic steatosis that became more stable and sever after 1 day of fasting and was associated with an opaque liver phenotype (dark under transmitted light). Unlike larvae, adult fish fed HCD for 14 days followed by a 3-day fast did not develop a stable fatty liver phenotype, though the fish had higher ApoB-LP levels in plasma and an upregulated lipogenesis gene fasn in adipose tissue. In conclusion, our HCD zebrafish protocol represents an effective and reliable approach for studying the temporal characteristics of the physiological and biochemical responses to high levels of dietary cholesterol and provides insights into the mechanisms that may underlie fatty liver disease.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100637"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A validated HPLC-MS/MS method for the simultaneous determination of ecdysteroid hormones in subminimal amounts of biological material. 一种有效的 HPLC-MS/MS 方法，用于同时测定微量生物材料中的蜕皮激素。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-05 DOI: 10.1016/j.jlr.2024.100640

Lucie Marešová, Martin Moos, Stanislav Opekar, Michalina Kazek, Clemens Eichler, Petr Šimek

{"title":"A validated HPLC-MS/MS method for the simultaneous determination of ecdysteroid hormones in subminimal amounts of biological material.","authors":"Lucie Marešová, Martin Moos, Stanislav Opekar, Michalina Kazek, Clemens Eichler, Petr Šimek","doi":"10.1016/j.jlr.2024.100640","DOIUrl":"10.1016/j.jlr.2024.100640","url":null,"abstract":"Ecdysteroids represent a large class of polyhydroxylated steroids which, due to their anabolic properties, are marketed as dietary supplements. Some ecdysteroids also act as important hormones in arthropods, where they regulate molting, development, and reproduction and many of these insects are miniature organisms that contain submicroliter levels of circulating biofluids. Analysis of ecdysteroids is further complicated by their very low abundance, large fluctuations during development, and difficult access to a pooled sample, which is important for quantitative measurements. In this work, we propose a new method that overcomes the described difficulties and allows validated quantification of four ecdysteroids in minimal amounts of biological material. After methanolic extraction, detectability of the ecdysteroids is increased 16- to 20-fold by conversion to their 14,15-anhydrooximes. These are further purified by pipette tip solid-phase extraction on a three-layer sorbent and subjected to HPLC-MS/MS analysis. Full validation was achieved using hemolymph from larvae of the firebug Pyrrhocoris apterus as a blank matrix and by the determination of ecdysteroids in a single Drosophila larva. The lower limit of quantifications for the four target ecdysteroids (20-hydroxyecdysone, ecdysone, makisterone A, and 2-deoxyecdysone) were 0.01; 0.1; 0.05; and 0.025 pg·ml-1 (20; 200; 100; 50 fmol ml-1), respectively, with very good accuracy, precision (expressed as relative standard deviation <15%) and recoveries (96%-119.9%). The application potential of the new method was demonstrated by quantification of ecdysteroids in various biological materials including human serum.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100640"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The sphingosine kinase 2 inhibitors ABC294640 and K145 elevate (dihydro)sphingosine 1-phosphate levels in various cells. 鞘氨醇激酶 2 抑制剂 ABC294640 和 K145 可提高各种细胞中的 1-磷酸（二氢）鞘氨醇水平。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-08-23 DOI: 10.1016/j.jlr.2024.100631

Agata Prell, Dominik Wigger, Andrea Huwiler, Fabian Schumacher, Burkhard Kleuser

{"title":"The sphingosine kinase 2 inhibitors ABC294640 and K145 elevate (dihydro)sphingosine 1-phosphate levels in various cells.","authors":"Agata Prell, Dominik Wigger, Andrea Huwiler, Fabian Schumacher, Burkhard Kleuser","doi":"10.1016/j.jlr.2024.100631","DOIUrl":"10.1016/j.jlr.2024.100631","url":null,"abstract":"Sphingosine kinases (SphKs), enzymes that produce the bioactive lipids dihydrosphingosine 1-phosphate (dhS1P) and sphingosine 1-phosphate (S1P), are associated with various diseases, including cancer and infections. For this reason, a number of SphK inhibitors have been developed. Although off-target effects have been described for selected agents, SphK inhibitors are mostly used in research without monitoring the effects on the sphingolipidome. We have now investigated the effects of seven commonly used SphK inhibitors (5c, ABC294640 (opaganib), N,N-dimethylsphingosine, K145, PF-543, SLM6031434, and SKI-II) on profiles of selected sphingolipids in Chang, HepG2, and human umbilical vein endothelial cells. While we observed the expected (dh)S1P reduction for N,N-dimethylsphingosine, PF-543, SKI-II, and SLM6031434, 5c showed hardly any effect. Remarkably, for K145 and ABC294640, both reported to be specific for SphK2, we observed dose-dependent strong increases in dhS1P and S1P across cell lines. Compensatory effects of SphK1 could be excluded, as this observation was also made in SphK1-deficient HK-2 cells. Furthermore, we observed effects on dihydroceramide desaturase activity for all inhibitors tested, as has been previously noted for ABC294640 and SKI-II. In additional mechanistic studies, we investigated the massive increase of dhS1P and S1P after short-term cell treatment with ABC294640 and K145 in more detail. We found that both compounds affect sphingolipid de novo synthesis, with 3-ketodihydrosphingosine reductase and dihydroceramide desaturase as their targets. Our study indicates that none of the seven SphK inhibitors tested was free of unexpected on-target and/or off-target effects. Therefore, it is important to monitor cellular sphingolipid profiles when SphK inhibitors are used in mechanistic studies.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100631"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Murine HSD17β13 does not control liver steatosis and modestly impacts fibrosis in a sex- and diet-specific manner. 小鼠 HSD17β13 不能控制肝脏脂肪变性，并以性别和饮食特异性的方式适度影响肝纤维化。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-08-24 DOI: 10.1016/j.jlr.2024.100634

Justin D Crane, Ornella Barrandon, Bryan Faherty, Matt Gorgoglione, Collin Crowley, Jeff Morin, Trenton T Ross, Jackson Shimkonis, Dongmei Li, Dinesh Hirenallur-Shanthappa, Magalie Boucher, Youngwook Ahn, Michelle F Clasquin

{"title":"Murine HSD17β13 does not control liver steatosis and modestly impacts fibrosis in a sex- and diet-specific manner.","authors":"Justin D Crane, Ornella Barrandon, Bryan Faherty, Matt Gorgoglione, Collin Crowley, Jeff Morin, Trenton T Ross, Jackson Shimkonis, Dongmei Li, Dinesh Hirenallur-Shanthappa, Magalie Boucher, Youngwook Ahn, Michelle F Clasquin","doi":"10.1016/j.jlr.2024.100634","DOIUrl":"10.1016/j.jlr.2024.100634","url":null,"abstract":"Human genetic studies show that loss of function mutations in 17-Beta hydroxysteroid dehydrogenase (HSD17β13) are associated with protection from non-alcoholic steatohepatitis (NASH). As a result, therapies that reduce HSD17β13 are being pursued for the treatment of NASH. However, inconsistent effects on steatosis, inflammation, and fibrosis pathogenesis have been reported in murine Hsd17b13 knockdown or knockout models. To clarify whether murine Hsd17b13 loss regulates liver damage and fibrosis, we characterized Hsd17b13 knockout mice subjected to pro-NASH diets or pro-inflammatory chemical-induced liver injury. There were no effects of Hsd17b13 loss on liver injury, inflammation, fibrosis, or lipids after 28 weeks on the Gubra-Amylin NASH (GAN) diet or 12 weeks on a 45% choline-deficient high-fat diet (CDAHFD). However, AAV-mediated re-expression of murine Hsd17b13 in KO mice increased liver macrophage abundance in both sexes fed the 45% CDAHFD. In contrast, there was a modest reduction in liver fibrosis, but not lipids or inflammation within Hsd17b13 null female, but not male, mice after 12 weeks of a 60% CDAHFD compared to WT littermates. Fibrosis and the abundance of liver macrophages were increased in Hsd17b13 KO females upon adenoviral re-expression of mouse HSD17β13, but this was not reflected in inflammatory markers. Additionally, we found minimal differences in liver injury, lipids, or inflammatory and fibrotic markers 48 h after acute CCl4 exposure. In summary, murine Hsd17b13 loss has modest diet- and sex-specific effects on liver fibrosis which contrasts with human genetic studies. This suggests a disconnect between the biological function of HSD17β13 in mice and humans.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100634"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11440797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxoplasma acyl-CoA synthetase TgACS3 is crucial to channel host fatty acids in lipid droplets and for parasite propagation. 弓形虫酰基-CoA 合成酶 TgACS3 对于引导脂滴中的宿主脂肪酸和寄生虫的繁殖至关重要。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-19 DOI: 10.1016/j.jlr.2024.100645

Sheena Dass, Serena Shunmugam, Sarah Charital, Samuel Duley, Christophe-Sébastien Arnold, Nicholas J Katris, Pierre Cavaillès, Marie-France Cesbron-Delauw, Yoshiki Yamaryo-Botté, Cyrille Y Botté

{"title":"Toxoplasma acyl-CoA synthetase TgACS3 is crucial to channel host fatty acids in lipid droplets and for parasite propagation.","authors":"Sheena Dass, Serena Shunmugam, Sarah Charital, Samuel Duley, Christophe-Sébastien Arnold, Nicholas J Katris, Pierre Cavaillès, Marie-France Cesbron-Delauw, Yoshiki Yamaryo-Botté, Cyrille Y Botté","doi":"10.1016/j.jlr.2024.100645","DOIUrl":"10.1016/j.jlr.2024.100645","url":null,"abstract":"Apicomplexa comprise important pathogenic parasitic protists that heavily depend on lipid acquisition to survive within their human host cells. Lipid synthesis relies on the incorporation of an essential combination of fatty acids (FAs) either generated by a metabolically adaptable de novo synthesis in the parasite or by scavenging from the host cell. The incorporation of FAs into membrane lipids depends on their obligate metabolic activation by specific enzyme groups, acyl-CoA synthetases (ACSs). Each ACS has its own specificity, so it can fulfill specific metabolic functions. Whilst such functionalities have been well studied in other eukaryotic models, their roles and importance in Apicomplexa are currently very limited, especially for Toxoplasma gondii. Here, we report the identification of seven putative ACSs encoded by the genome of T. gondii (TgACS), which localize to different sub-cellular compartments of the parasite, suggesting exclusive functions. We show that the perinuclear/cytoplasmic TgACS3 regulates the replication and growth of Toxoplasma tachyzoites. Conditional disruption of TgACS3 shows that the enzyme is required for parasite propagation and survival, especially under high host nutrient content. Lipidomic analysis of parasites lacking TgACS3 reveals its role in the activation of host-derived FAs that are used for i) parasite membrane phospholipid and ii) storage triacylglycerol (TAG) syntheses, allowing proper membrane biogenesis of parasite progenies. Altogether, our results reveal the role of TgACS3 as the bulk FA activator for membrane biogenesis allowing intracellular division and survival in T. gondii tachyzoites, further pointing to the importance of ACS and FA metabolism for the parasite.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100645"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The adipocyte apolipoprotein M is negatively associated with inflammation. 脂肪细胞载脂蛋白 M 与炎症呈负相关。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-19 DOI: 10.1016/j.jlr.2024.100648

Laurie Frances, Mikael Croyal, Soline Pittet, Léa Da Costa Fernandes, Milan Boulaire, Laurent Monbrun, Ellen E Blaak, Christina Christoffersen, Cédric Moro, Geneviève Tavernier, Nathalie Viguerie

{"title":"The adipocyte apolipoprotein M is negatively associated with inflammation.","authors":"Laurie Frances, Mikael Croyal, Soline Pittet, Léa Da Costa Fernandes, Milan Boulaire, Laurent Monbrun, Ellen E Blaak, Christina Christoffersen, Cédric Moro, Geneviève Tavernier, Nathalie Viguerie","doi":"10.1016/j.jlr.2024.100648","DOIUrl":"10.1016/j.jlr.2024.100648","url":null,"abstract":"Obesity is associated with the development of local adipose tissue (AT) and systemic inflammation. Most adipokines are upregulated with obesity and have pro-inflammatory properties. Few are downregulated and possess beneficial anti-inflammatory effects. The apolipoprotein M (APOM) is an adipokine whose expression is low during obesity and associated with a metabolically healthy AT. Here, the role of adipose-derived APOM on obesity-associated AT inflammation was investigated by measuring the expression of pro-inflammatory genes in human and mouse models. In 300 individuals with obesity, AT APOM mRNA level was negatively associated with plasma hs-CRP. The inflammatory profile was assessed in Apom-/- and WT mice fed a normal chow diet (NCD), or a high-fat diet (HFD) to induce AT inflammation. After HFD, mice had a higher inflammatory profile in AT and liver, and a 50% lower Apom gene expression compared with NCD-fed mice. Apom deficiency was associated with a higher inflammatory signature in AT compared with WT mice but not in the liver. Adeno-associated viruses encoding human APOM were used to induce APOM overexpression: in vivo, in WT mice AT prior to HFD; in vitro, in human adipocytes which conditioned media was applied to ThP-1 macrophages. The murine AT overexpressing APOM gene had a reduced inflammatory profile. The macrophages treated with APOM-enriched media from adipocytes exhibited lower IL6 and MCP1 gene expression compared with macrophages treated with control media, independently of S1P. Our study highlights the protective role of adipocyte APOM against obesity-induced AT inflammation.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100648"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0