{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:20:47Z","timestamp":1791429647733,"version":"4.3.3"},"reference-count":67,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","award":["RG1802\u201030121"],"award-info":[{"award-number":["RG1802\u201030121"]}],"id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS120877"],"award-info":[{"award-number":["R01NS120877"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS052741\u201010"],"award-info":[{"award-number":["R01NS052741\u201010"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS107946"],"award-info":[{"award-number":["R21NS107946"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM145408"],"award-info":[{"award-number":["T32GM145408"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Disruptions in the metabolism of cholesterol and other lipids are strongly implicated in the pathogenesis of neurological disease. The CNS is highly enriched in cholesterol, which is primarily synthesized\n                    <jats:italic>de novo<\/jats:italic>\n                    . Cholesterol synthesis is also rate limiting for myelin regeneration. Given that knockout of the thrombin receptor (Protease Activated Receptor 1 (PAR1)) accelerates myelin regeneration, here we sought to determine the potential regulatory actions of PAR1 in CNS cholesterol and lipid metabolism in the intact adult CNS and during myelin regeneration. We present quantitative PCR and RNAseq evidence from murine spinal cords at the peak of myelination and in adulthood showing PAR1 knockout is associated with increased gene expression for cholesterol biosynthesis (Hmgcs1, Hmgcr, Sqle, and Dhcr7), lipid transport (ApoE, Abca1, and Ldlr), and intracellular processing (Lcat, Npc1, and Npc2) at one or more time points examined. An upregulation of genes involved in the synthesis of other lipids enriched in the myelin membrane, specifically Fa2h, Ugt8a, and Gal3st1, was also observed in PAR1 knockouts. Transcription factors essential for lipid and cholesterol production (Srebf1 and Srebf2) were also increased in PAR1 knockout spinal cords at the postnatal day 21 peak of myelination and at day 45. GC\u2013MS and LC\u2013MS quantification of lipids demonstrated coordinate increases in the abundance of select cholesterol and lipid species in the spinal cords of PAR1 knockout mice, including enrichment of esterified cholesterol, together with sphingomyelins and sphingolipids. Co\u2010localization of the SREBP1 and SREBP2 transcription factors, as well as HMGCS1, a rate\u2010limiting enzyme in cholesterol biosynthesis, to glia during remyelination post\u2010lysolecithin or cuprizone\u2010mediated demyelination showed a prominent regulatory role for PAR1 in Olig2+ oligodendrocytes. PAR1 knockouts also demonstrated elevated levels of SREBP2 in more mature GST3+ oligodendrocytes and SREBP1 in GFAP+ astrocytes during remyelination post\u2010lysolecithin. These findings demonstrate novel roles for PAR1 as a regulator of CNS cholesterol and lipid metabolism and its potential as a therapeutic target to increase cholesterol availability to improve myelin regeneration.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70047-fig-0010-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70047","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T18:16:22Z","timestamp":1742840182000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Regulation of\n                    <scp>CNS<\/scp>\n                    Lipids by Protease Activated Receptor 1"],"prefix":"10.1111","volume":"169","author":[{"given":"Hyesook","family":"Yoon","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation Center for Regenerative Biotherapeutics  Rochester Minnesota USA"},{"name":"Department of Physiology and Biomedical Engineering  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Triplet","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Alix School of Medicine, and the Mayo Clinic Medical Scientist Training Program  Rochester USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lincoln","family":"Wurtz","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Alix School of Medicine, and the Mayo Clinic Medical Scientist Training Program  Rochester USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney L.","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation Center for Regenerative Biotherapeutics  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan\u2010Il","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation Center for Regenerative Biotherapeutics  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2395-589X","authenticated-orcid":false,"given":"Isobel A.","family":"Scarisbrick","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation Center for Regenerative Biotherapeutics  Rochester Minnesota USA"},{"name":"Department of Physiology and Biomedical Engineering  Rochester Minnesota USA"},{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Alix School of Medicine, and the Mayo Clinic Medical Scientist Training Program  Rochester USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.01.001"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R006338"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000120374.59826.1b"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.6216"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.03.007"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.5b04227"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu334"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22534"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002605"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4183"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.56.3.312"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201027613\u20109"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2009.035"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00248"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2021.101035"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14360-7"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.032068299"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1995.64020895.x"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-15-224"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24012"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.11.013"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22122"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2264-20.2021"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-3-r25"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2012.263"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.04.005"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01362-2"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.667673"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05383-z"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2001.tb00385.x"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.07999"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.12.029"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2022.104011"},{"key":"e_1_2_11_37_1","volume-title":"Lehninger Principles of Biochemistry","author":"Nelson D. L.","year":"2012"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.05917.x"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2008.06.025"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI123959"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2015.1043267"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040812"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn0403-345"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.37349\/ent.2022.00015"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.04.010"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.003491"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.08.003"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"e_1_2_11_49_1","first-page":"321","article-title":"Association of Apolipoprotein E Epsilon 4 Allele With Sporadic Late Onset Alzheimer's Disease. A Meta\u2010Analysis","volume":"17","author":"Sadigh\u2010Eteghad S.","year":"2012","journal-title":"Neurosciences"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-091922-034237"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1426"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.2c00330"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.626192"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms160716067"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2010682117"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105294"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905633106"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821306116"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.580599"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.175438"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2029-19.2019"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22788"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23215"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24100"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-014-0131-3"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay1809"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.03.003"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60467"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,13]],"date-time":"2025-04-13T13:53:47Z","timestamp":1744552427000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.70047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":67,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1111\/jnc.70047"],"URL":"https:\/\/doi.org\/10.1111\/jnc.70047","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/JNC.70047\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70047\/v2\/review1","asserted-by":"object"}]},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"2024-08-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70047"}}