Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice
Most cells acquire cholesterol by endocytosis of circulating low-density lipoproteins (LDLs). After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid...
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| Veröffentlicht in: | EMBO reports 2019-07, Vol.20 (7), p.e47055 |
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| creator | Moreau, Dimitri Vacca, Fabrizio Vossio, Stefania Scott, Cameron Colaco, Alexandria Paz Montoya, Jonathan Ferguson, Charles Damme, Markus Moniatte, Marc Parton, Robert G Platt, Frances M Gruenberg, Jean |
| description | Most cells acquire cholesterol by endocytosis of circulating low-density lipoproteins (LDLs). After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high-content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver of Npc1
mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC. |
| doi_str_mv | 10.15252/embr.201847055 |
| format | Article |
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mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.</description><identifier>ISSN: 1469-221X</identifier><identifier>EISSN: 1469-3178</identifier><identifier>DOI: 10.15252/embr.201847055</identifier><identifier>PMID: 31267706</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>Animals ; Cells, Cultured ; Cholesterol - metabolism ; Endosomes - drug effects ; Endosomes - metabolism ; Female ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; HeLa Cells ; Humans ; Lysophospholipids - metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Monoglycerides - metabolism ; Niemann-Pick Disease, Type C - metabolism ; Piperidines - pharmacology</subject><ispartof>EMBO reports, 2019-07, Vol.20 (7), p.e47055</ispartof><rights>2019 The Authors. Published under the terms of the CC BY 4.0 license.</rights><rights>2019 The Authors. Published under the terms of the CC BY 4.0 license</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-7494-5248 ; 0000-0003-3984-1395 ; 0000-0002-0300-4862</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607015/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607015/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31267706$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moreau, Dimitri</creatorcontrib><creatorcontrib>Vacca, Fabrizio</creatorcontrib><creatorcontrib>Vossio, Stefania</creatorcontrib><creatorcontrib>Scott, Cameron</creatorcontrib><creatorcontrib>Colaco, Alexandria</creatorcontrib><creatorcontrib>Paz Montoya, Jonathan</creatorcontrib><creatorcontrib>Ferguson, Charles</creatorcontrib><creatorcontrib>Damme, Markus</creatorcontrib><creatorcontrib>Moniatte, Marc</creatorcontrib><creatorcontrib>Parton, Robert G</creatorcontrib><creatorcontrib>Platt, Frances M</creatorcontrib><creatorcontrib>Gruenberg, Jean</creatorcontrib><title>Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><description>Most cells acquire cholesterol by endocytosis of circulating low-density lipoproteins (LDLs). After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high-content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver of Npc1
mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.</description><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Cholesterol - metabolism</subject><subject>Endosomes - drug effects</subject><subject>Endosomes - metabolism</subject><subject>Female</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Lysophospholipids - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Monoglycerides - metabolism</subject><subject>Niemann-Pick Disease, Type C - metabolism</subject><subject>Piperidines - pharmacology</subject><issn>1469-221X</issn><issn>1469-3178</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkElLA0EQhRtRjEbP3qT_wMReppe5CBJXCOpBwdtQ01NJWmejexLMv3eCUfRQvMd7Vd-hCDnjbMKVUOIC6yJMBOM2NUypPXLEU50lkhu7v_NC8LcROY7xnTGmMmMPyUhyoY1h-oh8XofVIvFNuXJYUt-4gBBxMLTaxLbwsVu2w0DvS-8oOF_SgNvlSPslUrdsK4w9hrai7RpD1cKWQh891tA0ybN3H7TfdEin1GFVRQpNSWvv8IQczKGKeLrTMXm9vXmZ3iezp7uH6dUs6biWfSKNAWcdSM3QZkoxkTortZgX1ha2kKlRAGyIpeACCkiztMwkzNECSMONHJPLb263KmosHTZ9gCrvgq8hbPIWfP6_afwyX7TrXGtmGFcD4Pwv4Pfy54fyC6Scdyc</recordid><startdate>20190701</startdate><enddate>20190701</enddate><creator>Moreau, Dimitri</creator><creator>Vacca, Fabrizio</creator><creator>Vossio, Stefania</creator><creator>Scott, Cameron</creator><creator>Colaco, Alexandria</creator><creator>Paz Montoya, Jonathan</creator><creator>Ferguson, Charles</creator><creator>Damme, Markus</creator><creator>Moniatte, Marc</creator><creator>Parton, Robert G</creator><creator>Platt, Frances M</creator><creator>Gruenberg, Jean</creator><general>John Wiley and Sons Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7494-5248</orcidid><orcidid>https://orcid.org/0000-0003-3984-1395</orcidid><orcidid>https://orcid.org/0000-0002-0300-4862</orcidid></search><sort><creationdate>20190701</creationdate><title>Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice</title><author>Moreau, Dimitri ; Vacca, Fabrizio ; Vossio, Stefania ; Scott, Cameron ; Colaco, Alexandria ; Paz Montoya, Jonathan ; Ferguson, Charles ; Damme, Markus ; Moniatte, Marc ; Parton, Robert G ; Platt, Frances M ; Gruenberg, Jean</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p163t-377ac8ca360e8955024c8362fb88b8b3475aa05023212aba494d93afe8aa37173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Cholesterol - metabolism</topic><topic>Endosomes - drug effects</topic><topic>Endosomes - metabolism</topic><topic>Female</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Lysophospholipids - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Monoglycerides - metabolism</topic><topic>Niemann-Pick Disease, Type C - metabolism</topic><topic>Piperidines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moreau, Dimitri</creatorcontrib><creatorcontrib>Vacca, Fabrizio</creatorcontrib><creatorcontrib>Vossio, Stefania</creatorcontrib><creatorcontrib>Scott, Cameron</creatorcontrib><creatorcontrib>Colaco, Alexandria</creatorcontrib><creatorcontrib>Paz Montoya, Jonathan</creatorcontrib><creatorcontrib>Ferguson, Charles</creatorcontrib><creatorcontrib>Damme, Markus</creatorcontrib><creatorcontrib>Moniatte, Marc</creatorcontrib><creatorcontrib>Parton, Robert G</creatorcontrib><creatorcontrib>Platt, Frances M</creatorcontrib><creatorcontrib>Gruenberg, Jean</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moreau, Dimitri</au><au>Vacca, Fabrizio</au><au>Vossio, Stefania</au><au>Scott, Cameron</au><au>Colaco, Alexandria</au><au>Paz Montoya, Jonathan</au><au>Ferguson, Charles</au><au>Damme, Markus</au><au>Moniatte, Marc</au><au>Parton, Robert G</au><au>Platt, Frances M</au><au>Gruenberg, Jean</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice</atitle><jtitle>EMBO reports</jtitle><addtitle>EMBO Rep</addtitle><date>2019-07-01</date><risdate>2019</risdate><volume>20</volume><issue>7</issue><spage>e47055</spage><pages>e47055-</pages><issn>1469-221X</issn><eissn>1469-3178</eissn><abstract>Most cells acquire cholesterol by endocytosis of circulating low-density lipoproteins (LDLs). 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| subjects | Animals Cells, Cultured Cholesterol - metabolism Endosomes - drug effects Endosomes - metabolism Female Fibroblasts - drug effects Fibroblasts - metabolism HeLa Cells Humans Lysophospholipids - metabolism Male Mice Mice, Inbred BALB C Monoglycerides - metabolism Niemann-Pick Disease, Type C - metabolism Piperidines - pharmacology |
| title | Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice |
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