Journal of Lipid Research最新文献_第2页

ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis. ACAT1/SOAT1 通过调节胆固醇平衡维持前脂肪细胞的成脂能力。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-29 DOI: 10.1016/j.jlr.2024.100680

Qing Liu, Xiaolin Wu, Wei Duan, Xiaohan Pan, Martin Wabitsch, Ming Lu, Jing Li, Li-Hao Huang, Zhangsen Zhou, Yuyan Zhu

{"title":"ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis.","authors":"Qing Liu, Xiaolin Wu, Wei Duan, Xiaohan Pan, Martin Wabitsch, Ming Lu, Jing Li, Li-Hao Huang, Zhangsen Zhou, Yuyan Zhu","doi":"10.1016/j.jlr.2024.100680","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100680","url":null,"abstract":"Maintaining cholesterol homeostasis is critical for preserving adipocyte function during the progression of obesity. Despite this, the regulatory role of cholesterol esterification in governing adipocyte expandability has been understudied. Acyl-coenzyme A (CoA):cholesterol acyltransferase / Sterol O-acyltransferase 1 (ACAT1/SOAT1) is the dominant enzyme to synthesize cholesteryl ester in most tissues. Our previous study demonstrated that knockdown of either ACAT1 or ACAT2 impaired adipogenesis. However, the underlying mechanism of how ACAT1 mediates adipogenesis remains unclear. Here, we reported that ACAT1 is the dominant isoform in white adipose tissue of both humans and mice and knocking out ACAT1 reduced fat mass in mice. Furthermore, ACAT1-deficiency inhibited the early stage of adipogenesis via attenuating PPARγ pathway. Mechanistically, ACAT1 deficiency inhibited SREBP2-mediated cholesterol uptake and thus reduced intracellular and plasma membrane cholesterol level during adipogenesis. While replenishing cholesterol could rescue adipogenic master gene - Pparγ's transcription in ACAT1 deficient cells during adipogenesis. Finally, overexpression of catalytically functional ACAT1, not the catalytic-dead ACAT1, rescued cholesterol level and efficiently rescued the transcription of PPARγ, as well as the adipogenesis in ACAT1-deficient preadipocytes. In summary, our study revealed the indispensable role of ACAT1 in adipogenesis via regulating intracellular cholesterol homeostasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100680"},"PeriodicalIF":5.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558068","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

Diet, β-glucocerebrosidase deficiency, and Parkinson's disease. 饮食、β-葡糖脑苷脂缺乏症和帕金森病。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-26 DOI: 10.1016/j.jlr.2024.100689

James A Shayman

引用次数: 0

Toxoplasma gondii Sustains Survival by Regulating Cholesterol Biosynthesis and Uptake via SREBP2 Activation. 弓形虫通过 SREBP2 激活调节胆固醇的合成和吸收维持生存

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100684

Yi-Min Fan, Qing-Qi Zhang, Ming Pan, Zhao-Feng Hou, Lizhi Fu, Xiulong Xu, Si-Yang Huang

{"title":"Toxoplasma gondii Sustains Survival by Regulating Cholesterol Biosynthesis and Uptake via SREBP2 Activation.","authors":"Yi-Min Fan, Qing-Qi Zhang, Ming Pan, Zhao-Feng Hou, Lizhi Fu, Xiulong Xu, Si-Yang Huang","doi":"10.1016/j.jlr.2024.100684","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100684","url":null,"abstract":"Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that cannot biosynthesize cholesterol via the mevalonate pathway, it sources this lipid from its host. We discovered that T. gondii infection upregulated the expression of host cholesterol synthesis related genes HMG-CoA reductase(HMGCR), squalene epoxidase (SQLE) and dehydrocholesterol reductase-7 (DHCR7), and increased the uptake pathway gene low-density lipoprotein receptor (LDLR). We found a protein, sterol regulatory element binding protein 2 (SREBP2), which is the key protein regulating the host cholesterol synthesis and uptake during T. gondii infection. T. gondii induced a dose-dependent nuclear translocation of SREBP2. Knockdown SREBP2 reduced T. gondii-induced cholesterol biosynthesis and uptake. Consequently, the parasite's ability to acquire cholesterol was significantly diminished, impairing its invasion, replication, and bradyzoites development. Interfering cholesterol metabolism using AY9944 effectively inhibited T. gondii replication. In summary, SREBP2 played an important role in T. gondii infection in vitro, serving as a potential target for regulating T. gondii-induced cholesterol metabolism, offering insights into the prevention and treatment of toxoplasmosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100684"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568869","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

Differential impact of eicosapentaenoic acid and docosahexaenoic acid in an animal model of Alzheimer's disease. 二十碳五烯酸和二十二碳六烯酸对阿尔茨海默病动物模型的不同影响

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100682

Méryl-Farelle Oye Mintsa Mi-Mba, Meryem Lebbadi, Waël Alata, Carl Julien, Vincent Emond, Cyntia Tremblay, Samuel Fortin, Colin J Barrow, Jean-François Bilodeau, Frédéric Calon

{"title":"Differential impact of eicosapentaenoic acid and docosahexaenoic acid in an animal model of Alzheimer's disease.","authors":"Méryl-Farelle Oye Mintsa Mi-Mba, Meryem Lebbadi, Waël Alata, Carl Julien, Vincent Emond, Cyntia Tremblay, Samuel Fortin, Colin J Barrow, Jean-François Bilodeau, Frédéric Calon","doi":"10.1016/j.jlr.2024.100682","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100682","url":null,"abstract":"Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) improves cognitive performance in several animal models of Alzheimer's disease (AD), an effect often associated with reduced amyloid-beta (Aβ) and/or tau pathologies. However, it remains unclear to what extent eicosapentaenoic (EPA) provides additional benefits compared to docosahexaenoic acid (DHA). Here, male and female 3xTg-AD mice were fed for 3 months (13 to 16 months of age) the following diets: (1) control (no DHA/EPA), (2) DHA (1.1g/kg) and low EPA (0.4g/kg), or (3) DHA (0.9g/kg) with high EPA (9.2g/kg). The DHA and DHA+EPA diets respectively increased DHA by 19% and 8% in the frontal cortex of 3xTg-AD mice, compared to controls. Levels of EPA, which were below the detection limit after the control diet, reached 0.14% and 0.29% of total brain fatty acids after the DHA and DHA+EPA diet, respectively. DHA and DHA+EPA diets lowered brain arachidonic acid (ARA) levels and the n-6:n-3 docosapentaenoic acid (DPA) ratio. Brain uptake of free 14C-DHA measured through intracarotid brain perfusion, but not of 14C-EPA, was lower in 3xTg-AD compared to NonTg mice. DHA and DHA+EPA diets in 3xTg-AD mice reduced cortical soluble phosphorylated tau (pS202) (-34% high-DHA, -34% DHA+EPA, p<0.05) while increasing p21 activated kinase (+58% and +83%, p<0.001; respectively). High EPA intake lowered insoluble phosphorylated tau (-31% versus DHA, p<0.05). No diet effect on Aβ levels was observed. In conclusion, dietary intake of DHA and EPA leads to differential changes in brain PUFA while altering cerebral biomarkers consistent with beneficial effects against AD-like neuropathology.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100682"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568848","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

Effects of coconut oil, olive oil, and butter on plasma fatty acids and metabolic risk factors: a randomised trial. 椰子油、橄榄油和黄油对血浆脂肪酸和代谢风险因素的影响：随机试验。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100681

Solomon A Sowah, Albert Koulman, Stephen J Sharp, Fumiaki Imamura, Kay-Tee Khaw, Nita G Forouhi

{"title":"Effects of coconut oil, olive oil, and butter on plasma fatty acids and metabolic risk factors: a randomised trial.","authors":"Solomon A Sowah, Albert Koulman, Stephen J Sharp, Fumiaki Imamura, Kay-Tee Khaw, Nita G Forouhi","doi":"10.1016/j.jlr.2024.100681","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100681","url":null,"abstract":"There is limited evidence on the effects of different dietary sources of fats on detailed blood fatty acids (FAs). We aimed to evaluate the effects of coconut oil, olive oil and butter on circulating FA concentrations, and examine the associations between changes in plasma FAs and changes in metabolic markers. We conducted secondary analyses in the COB (coconut oil, olive oil and butter) Trial that evaluated 96 healthy adults in a 4-week parallel randomised controlled trial of three dietary interventions: 50 g/d of extra-virgin coconut oil (n=30), extra-virgin olive oil (n=33) or unsalted butter (n=33). We measured plasma phospholipid FA concentrations (mol% of total) using gas-chromatography. Using linear regression, we estimated the effects of the interventions on changes in FAs and the associations of changes in selected FAs with changes in metabolic markers. Coconut oil doubled lauric acid (C12:0) and myristic acid (C14:0), butter increased those to a lesser extent, and olive oil reduced those. β (95% confidence interval) for changes in C12:0 comparing coconut oil to butter and olive oil were +0.04 (0.03-0.05) and +0.05 (0.04-0.06) mol%, respectively; for C14:0, +0.24 (0.17-0.32) and +0.37 (0.29-0.45), respectively. Olive oil increased oleic acid (OA) approximately by 1 mol%, while coconut oil and butter had little effect on OA. Butter increased odd-chain SFAs and trans-FAs while olive oil and coconut oil decreased them. Changes in FAs mostly showed no significant associations with changes in metabolic markers. The interventions of equal amounts of different food FA sources altered circulating FA concentrations differently.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100681"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568849","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

Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation. Orm 蛋白通过 LCB 介导的 Ypk1 调节来控制神经酰胺的合成和内吞。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100683

Jihui Ren, Robert Rieger, Nivea Pereira de Sa, Douglas Kelapire, Maurizio Del Poeta, Yusuf A Hannun

{"title":"Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation.","authors":"Jihui Ren, Robert Rieger, Nivea Pereira de Sa, Douglas Kelapire, Maurizio Del Poeta, Yusuf A Hannun","doi":"10.1016/j.jlr.2024.100683","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100683","url":null,"abstract":"Sphingolipids (SPLs) are major components of cell membranes with significant functions. Their production is a highly-regulated multi-step process with the formation of two major intermediates, long chain bases (LCBs) and ceramides. Homologous Orm proteins in both yeast and mammals negatively regulate LCB production by inhibiting serine palmitoyltransferase (SPT), the first enzyme in SPL de novo synthesis. Orm proteins are therefore regarded as major regulator of SPL production. Combining targeted lipidomic profiling with phenotypic analysis of yeast mutants with both ORM1 and ORM2 deleted (orm1/2Δ), we report here that Ypk1, an AGC family protein kinase, signaling is compromised in an LCB-dependent manner. In orm1/2Δ, phosphorylation of Ypk1 at its activation sites is reduced, so does its in vivo activity shown by reduced phosphorylation of Ypk1 substrate, Lac1, the catalytic component of ceramide synthase (CerS). A corresponding defect in ceramide synthesis was detected, preventing the extra LCBs generated in orm1/2Δ from fully converting into downstream SPL products. The results suggest that Orm proteins play a complex role in regulating SPL production in yeast S. cerevisiae by exerting an extra and opposite effect on CerS. Functionally, we define an endocytosis and an actin polarization defect of orm1/2Δ and demonstrate the roles of Ypk1 in mediating the effects of Orm proteins on endocytosis. Collectively, the results reveal a previously unrecognized complexity of SPL de novo synthesis pathway and point to a potential role of Orm proteins as upstream regulators to control Ypk1-mediated biological functions via regulating LCB production.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100683"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568860","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

Untargeted Lipidomics Reveals Novel HDL Metabotypes and Lipid-Clinical Correlates. 非靶向血脂组学揭示新型高密度脂蛋白代谢型和血脂临床相关性

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100678

Peer W F Karmaus, Scott M Gordon, Marcus Y Chen, Alison A Motsinger-Reif, Rodney W Snyder, Timothy R Fennell, Suramya Waidyanatha, Reshan A Fernando, Alan T Remaley, Michael B Fessler

{"title":"Untargeted Lipidomics Reveals Novel HDL Metabotypes and Lipid-Clinical Correlates.","authors":"Peer W F Karmaus, Scott M Gordon, Marcus Y Chen, Alison A Motsinger-Reif, Rodney W Snyder, Timothy R Fennell, Suramya Waidyanatha, Reshan A Fernando, Alan T Remaley, Michael B Fessler","doi":"10.1016/j.jlr.2024.100678","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100678","url":null,"abstract":"Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein referred to as HDL 'metabotypes'. Subjects in metabotype 1 were likelier to be female and tended to have a less atherogenic lipoprotein profile, higher HDL cholesterol efflux capacity (CEC), and lower-grade non-calcified burden on coronary imaging than metabotype 2 counterparts. Specific lipids were relatively enriched in metabotype 1 HDL. Linear modeling revealed that several of these lipids were positively associated with CEC, statin use, HDL size, and HDL particle number, and positively correlated with HDL apolipoprotein A-1, suggesting that they may be informative HDL biomarkers. Taken together, we posit a novel, clinically relevant categorization for HDL revealed by systems biology.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100678"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568871","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

Liver proteomics identifies a disconnect between proteins associated with de novo lipogenesis and triglyceride storage. 肝脏蛋白质组学发现，与新脂肪生成和甘油三酯储存相关的蛋白质之间存在脱节。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100687

Lewin Small, Tuong-Vi Nguyen, Mark Larance, Darren N Saunders, Andrew J Hoy, Carsten Schmitz-Peiffer, Gregory J Cooney, Amanda E Brandon

{"title":"Liver proteomics identifies a disconnect between proteins associated with de novo lipogenesis and triglyceride storage.","authors":"Lewin Small, Tuong-Vi Nguyen, Mark Larance, Darren N Saunders, Andrew J Hoy, Carsten Schmitz-Peiffer, Gregory J Cooney, Amanda E Brandon","doi":"10.1016/j.jlr.2024.100687","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100687","url":null,"abstract":"De novo lipogenesis (DNL) has been implicated in the development and progression of liver steatosis. Hepatic DNL is strongly influenced by dietary macronutrient composition with diets high in carbohydrate increasing DNL and while diets high in fat decrease DNL. The enzymes in the core DNL pathway have been well characterised, however less is known about other liver proteins that play accessory or regulatory roles. In the current study, we associate measured rates of hepatic DNL and fat content with liver proteomic analysis in mice to identify known and unknown proteins that may have a role in DNL. Male mice were fed either a standard chow diet, a semi-purified high starch or high fat diet. Both semi-purified diets resulted in increased body weight, fat mass and liver triglyceride content compared to chow controls and hepatic DNL was increased in the high starch and decreased in high fat fed mice. Proteomic analysis identified novel proteins associated with DNL that are involved in taurine metabolism, suggesting a link between these pathways. There was no relationship between proteins that associated with DNL and those associated with liver triglyceride content. Further analysis identified proteins that are differentially regulated when comparing a non-purified chow diet to either of the semi-purified diets which provide a set of proteins that are influenced by dietary complexity. Finally, we compared the liver proteome between 4- and 30-week diet-fed mice and found remarkable similarity suggesting metabolic remodelling of the liver occurs rapidly in response to differing dietary components.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100687"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568856","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

APOA2 Increases Cholesterol Efflux Capacity to Plasma HDL by Displacing the C-terminus of Resident APOA1. APOA2 通过置换驻留 APOA1 的 C-末端来增加血浆高密度脂蛋白的胆固醇外排能力。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100686

Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E Street, Stephanie M Thibert, Isaac K Attah, Chelsea M Hutchinson Bunch, Irina Novikova, James Evans, Amy S Shah, Scott M Gordon, Jere P Segrest, Karin E Bornfeldt, Tomas Vaisar, Jay W Heinecke, W Sean Davidson, John T Melchior

{"title":"APOA2 Increases Cholesterol Efflux Capacity to Plasma HDL by Displacing the C-terminus of Resident APOA1.","authors":"Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E Street, Stephanie M Thibert, Isaac K Attah, Chelsea M Hutchinson Bunch, Irina Novikova, James Evans, Amy S Shah, Scott M Gordon, Jere P Segrest, Karin E Bornfeldt, Tomas Vaisar, Jay W Heinecke, W Sean Davidson, John T Melchior","doi":"10.1016/j.jlr.2024.100686","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100686","url":null,"abstract":"The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity (CEC). APOA2 likewise increased the CEC of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up experiments with reconstituted HDL corroborated that the presence of both APOA1 and APOA2 were necessary for the increased efflux. Using limited proteolysis and chemical cross-linking mass spectrometry, we found that APOA2 induced a conformational change in the N- and C-terminal helices of APOA1. Using reconstituted HDL with APOA1 deletion mutants, we further showed that APOA2 lost its ability to stimulate ABCA1 efflux to HDL if the C-terminal domain of APOA1 was absent, but retained this ability when the N-terminal domain was absent. Based on these findings, we propose a model in which APOA2 displaces the C-terminal helix of APOA1 from the HDL surface which can then interact with ABCA1 - much like it does in lipid-poor APOA1. These findings suggest APOA2 may be a novel therapeutic target given this ability to open a large, high-capacity pool of HDL particles to enhance ABCA1-mediated cholesterol efflux.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100686"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568843","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

Resolvin D2/GPR 18 axis ameliorates pressure overload-induced heart failure by inhibiting pro-inflammatory macrophage polarization. Resolvin D2/GPR 18 轴通过抑制促炎性巨噬细胞极化来改善压力过载引起的心力衰竭。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100679

Zihui Zheng, Mengmeng Zhao, Yao Xu, Jishou Zhang, Shanshan Peng, Jianfang Liu, Wei Pan, Zheng Yin, Cheng Wei, Juan-Juan Qin, Jun Wan, Menglong Wang

{"title":"Resolvin D2/GPR 18 axis ameliorates pressure overload-induced heart failure by inhibiting pro-inflammatory macrophage polarization.","authors":"Zihui Zheng, Mengmeng Zhao, Yao Xu, Jishou Zhang, Shanshan Peng, Jianfang Liu, Wei Pan, Zheng Yin, Cheng Wei, Juan-Juan Qin, Jun Wan, Menglong Wang","doi":"10.1016/j.jlr.2024.100679","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100679","url":null,"abstract":"Accumulating evidence has revealed that chronic unresolved inflammation can cause significant tissue damage and can be a key mediator of advanced heart failure (HF). Resolvin (Rv) D2, a member of specialized pro-resolving lipid mediators (SPMs), plays a protective role in various diseases by facilitating resolution. However, whether RvD2 participates in the pathogenesis of HF is still unclear. Our study demonstrated that RvD2 treatment mitigated cardiac remodeling and improved cardiac function in HF mice induced by pressure overload. The absence of G protein-coupled receptor 18 (GPR18), an endogenous receptor for RvD2, abolished the beneficial effects of RvD2 on HF. Additionally, RvD2 inhibited inflammatory responses and Ly6Chigh macrophage polarization during both early and late inflammatory stages involved in HF. Further investigation revealed that bone marrow transplantation from GPR18 deficient mice into WT mice blocked the protective effects of RvD2 in HF mice. Moreover, GPR18 deficiency impeded RvD2's capacity to downregulate inflammatory responses and Ly6Chigh macrophage polarization. Consistent with experiments in vivo, RvD2 treatment in bone marrow-derived macrophages (BMDMs) reduced inflammatory responses through its receptor GPR18. Mechanistically, RvD2 suppressed the phosphorylation of STAT1 and NF-κB p65, and the effects of RvD2 were reversed by the application of STAT1 or NF-κB p65 agonists in BMDMs. In conclusion, RvD2/GPR18 axis improved cardiac remodeling and function in pressure overload-induced HF mice by modulating macrophages phenotype via STAT1 and NF-κB p65 pathways. Our findings underscore the anti-inflammatory potential of RvD2/GPR18 axis, which may be a promising strategy for reducing the burden of HF.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100679"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568865","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