{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:44:41Z","timestamp":1791848681265,"version":"4.3.4"},"reference-count":28,"publisher":"Portland Press Ltd.","issue":"5","license":[{"start":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T00:00:00Z","timestamp":1582502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,3,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE\u2212\/\u2212) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.<\/jats:p>","DOI":"10.1042\/cs20191028","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T06:59:09Z","timestamp":1582527549000},"page":"439-458","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Myriocin and\n                    <scp>d<\/scp>\n                    -PDMP ameliorate atherosclerosis in ApoE\u2212\/\u2212 mice via reducing lipid uptake and vascular inflammation"],"prefix":"10.1042","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9658-4869","authenticated-orcid":false,"given":"Zemou","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyue","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Institute of Analytical Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingbing","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Hospital, National Center of Gerontology, No.1 Dahua Road, Dong Dan, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Nan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Bai","sequence":"additional","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Institute of Analytical Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"key":"2021113011102688500_B1","doi-asserted-by":"publisher","first-page":"e1144","DOI":"10.1161\/CIR.0000000000000626","article-title":"Systematic review for the 2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"139","author":"Wilson","year":"2019","journal-title":"Circulation"},{"key":"2021113011102688500_B2","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41569-019-0171-8","article-title":"Statin efficacy in primary CVD prevention might diminish with patient age","volume":"16","author":"Fernandez-Ruiz","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"2021113011102688500_B3","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1111\/bcp.13898","article-title":"Associations of statin use with glycaemic traits and incident type 2 diabetes","volume":"85","author":"Ahmadizar","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"2021113011102688500_B4","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.2337\/dbi18-0018","article-title":"Strong heart, low ceramides","volume":"67","author":"Holland","year":"2018","journal-title":"Diabetes"},{"key":"2021113011102688500_B5","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.cmet.2017.12.003","article-title":"Could ceramides become the new cholesterol?","volume":"27","author":"Summers","year":"2018","journal-title":"Cell Metab."},{"key":"2021113011102688500_B6","doi-asserted-by":"publisher","first-page":"3465","DOI":"10.1161\/01.CIR.0000148370.60535.22","article-title":"Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice","volume":"110","author":"Park","year":"2004","journal-title":"Circulation"},{"key":"2021113011102688500_B7","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1172\/JCI60415","article-title":"Myeloid cell-specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis","volume":"123","author":"Chakraborty","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2021113011102688500_B8","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nrm.2017.107","article-title":"Sphingolipids and their metabolism in physiology and disease","volume":"19","author":"Hannun","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021113011102688500_B9","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1194\/jlr.E800005-JLR200","article-title":"Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice","volume":"49","author":"Glaros","year":"2008","journal-title":"J. Lipid Res."},{"key":"2021113011102688500_B10","doi-asserted-by":"publisher","first-page":"2403","DOI":"10.1161\/CIRCULATIONAHA.113.007559","article-title":"Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E-\/- mice and rabbits fed a high-fat and -cholesterol diet","volume":"129","author":"Chatterjee","year":"2014","journal-title":"Circulation"},{"key":"2021113011102688500_B11","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1161\/ATVBAHA.109.201673","article-title":"Inhibition of glycosphingolipid synthesis induces a profound reduction of plasma cholesterol and inhibits atherosclerosis development in APOE*3 Leiden and low-density lipoprotein receptor-\/- mice","volume":"30","author":"Bietrix","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113011102688500_B12","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1161\/CIRCULATIONAHA.117.029435","article-title":"The low-density lipoprotein receptor genotype is a significant determinant of the rebound in low-density lipoprotein cholesterol concentration after lipoprotein apheresis among patients with homozygous familial hypercholesterolemia","volume":"136","author":"Drouin-Chartier","year":"2017","journal-title":"Circulation"},{"key":"2021113011102688500_B13","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1042\/CS20180911","article-title":"Potential therapeutic targets for atherosclerosis in sphingolipid metabolism","volume":"133","author":"Yu","year":"2019","journal-title":"Clin. Sci."},{"key":"2021113011102688500_B14","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1002\/hep.23175","article-title":"Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice","volume":"50","author":"Bijl","year":"2009","journal-title":"Hepatology"},{"key":"2021113011102688500_B15","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1126\/science.aav3722","article-title":"Targeting a ceramide double bond improves insulin resistance and hepatic steatosis","volume":"365","author":"Chaurasia","year":"2019","journal-title":"Science"},{"key":"2021113011102688500_B16","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1161\/CIRCULATIONAHA.118.034083","article-title":"Protein kinase C via activating transcription factor 2-mediated CD36 expression and foam cell formation of Ly6C(hi) cells contributes to atherosclerosis","volume":"138","author":"Raghavan","year":"2018","journal-title":"Circulation"},{"key":"2021113011102688500_B17","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41467-018-07895-3","article-title":"CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGgamma","volume":"10","author":"Fan","year":"2019","journal-title":"Nat. Commun."},{"key":"2021113011102688500_B18","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.tem.2016.09.001","article-title":"Perilipin 2 and age-related metabolic diseases: a new perspective","volume":"27","author":"Conte","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"2021113011102688500_B19","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.atherosclerosis.2013.01.041","article-title":"Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction","volume":"228","author":"Dekker","year":"2013","journal-title":"Atherosclerosis"},{"key":"2021113011102688500_B20","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1161\/CIRCULATIONAHA.119.039697","article-title":"Targeting Filamin A reduces macrophage activity and atherosclerosis","volume":"140","author":"Bandaru","year":"2019","journal-title":"Circulation"},{"key":"2021113011102688500_B21","doi-asserted-by":"publisher","first-page":"2702","DOI":"10.1016\/j.celrep.2018.02.034","article-title":"Ceramide-protein interactions modulate ceramide-associated lipotoxic cardiomyopathy","volume":"22","author":"Walls","year":"2018","journal-title":"Cell Rep."},{"key":"2021113011102688500_B22","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/j.cmet.2016.10.002","article-title":"Adipocyte ceramides regulate subcutaneous adipose browning, inflammation, and metabolism","volume":"24","author":"Chaurasia","year":"2016","journal-title":"Cell Metab."},{"key":"2021113011102688500_B23","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.biomaterials.2015.06.001","article-title":"Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor","volume":"64","author":"Mishra","year":"2015","journal-title":"Biomaterials"},{"key":"2021113011102688500_B24","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1161\/ATVBAHA.119.313138","article-title":"Ly6C(+) inflammatory monocyte differentiation partially mediates hyperhomocysteinemia-induced vascular dysfunction in type 2 Diabetic db\/db mice","volume":"39","author":"Fang","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113011102688500_B25","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1161\/CIRCULATIONAHA.118.038571","article-title":"Caveolin-1 regulates atherogenesis by attenuating LDL transcytosis and vascular inflammation independent of endothelial nitric oxide synthase activation","volume":"140","author":"RamIrez","year":"2019","journal-title":"Circulation"},{"key":"2021113011102688500_B26","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1016\/j.cell.2019.05.008","article-title":"CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity","volume":"177","author":"Hammerschmidt","year":"2019","journal-title":"Cell"},{"key":"2021113011102688500_B27","doi-asserted-by":"publisher","first-page":"e4723","DOI":"10.1371\/journal.pone.0004723","article-title":"Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation","volume":"4","author":"van Eijk","year":"2009","journal-title":"PLoS ONE"},{"key":"2021113011102688500_B28","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.2337\/db18-0999","article-title":"Statins promote interleukin-1beta-dependent adipocyte insulin resistance through lower prenylation, not cholesterol","volume":"68","author":"Henriksbo","year":"2019","journal-title":"Diabetes"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/134\/5\/439\/869020\/cs-2019-1028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/134\/5\/439\/869020\/cs-2019-1028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T07:09:26Z","timestamp":1638256166000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/134\/5\/439\/222190\/Myriocin-and-d-PDMP-ameliorate-atherosclerosis-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3]]},"references-count":28,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,3,13]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20191028","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,3]]},"published":{"date-parts":[[2020,3]]}}}