{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:49:58Z","timestamp":1792900198489,"version":"4.5.0"},"reference-count":55,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T00:00:00Z","timestamp":1742428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011747","name":"Novo Nordisk Foundation Center for Basic Metabolic Research","doi-asserted-by":"publisher","award":["NNF20OC0063444"],"award-info":[{"award-number":["NNF20OC0063444"]}],"id":[{"id":"10.13039\/501100011747","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["23CVD02 19CVD04"],"award-info":[{"award-number":["23CVD02 19CVD04"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL171737 R01HL162698 R35HL139725 P01HL146358 R01HL087228"],"award-info":[{"award-number":["R01HL171737 R01HL162698 R35HL139725 P01HL146358 R01HL087228"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The John and Birthe Meyer Foundation","award":["100"],"award-info":[{"award-number":["100"]}],"id":[{"id":"https:\/\/ror.org\/03j077d81","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,25]]},"abstract":"<jats:p>\n                    Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3\/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3\/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3\/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen\u2013deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3\/8 and ANGPTL3 use the proximal portion of their N-terminal \u03b1-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL\u2019s\n                    <jats:italic>\u03b1\/\u03b2<\/jats:italic>\n                    -hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from unfolding and inactivation, particularly against the unfolding triggered by ANGPTL3. Pulse-labeling HDX-MS studies revealed that ANGPTL3\/8 and ANGPTL3\n                    <jats:italic>catalyze<\/jats:italic>\n                    LPL unfolding in an ATP-independent fashion, which categorizes these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3\/8 explains why low plasma concentrations of ANGPTL3\/8 are effective in inhibiting a molar excess of LPL in capillaries.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2420721122","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T18:26:18Z","timestamp":1742495178000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["ANGPTL3\/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-269X","authenticated-orcid":false,"given":"Anni","family":"Kumari","sequence":"first","affiliation":[{"name":"Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet","place":["Copenhagen N, Denmark"]},{"name":"Finsen Laboratory, Biotechnology Research and Innovation Centre, University of Copenhagen","place":["Copenhagen N, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne W. R.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Biotechnology Research and Innovation Centre, University of Copenhagen","place":["Copenhagen N, Denmark"]},{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark","place":["Odense M, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Signe","family":"Bondesen","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Biotechnology Research and Innovation Centre, University of Copenhagen","place":["Copenhagen N, Denmark"]},{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark","place":["Odense M, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0584-4723","authenticated-orcid":false,"given":"Yuewei","family":"Qian","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories, Eli Lilly and Company","place":["Indianapolis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao D.","family":"Tian","sequence":"additional","affiliation":[{"name":"Laboratory of Lipoprotein Metabolism, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney G.","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Iowa","place":["Iowa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7168-8522","authenticated-orcid":false,"given":"Brandon S. J.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Iowa","place":["Iowa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan T.","family":"Remaley","sequence":"additional","affiliation":[{"name":"Laboratory of Lipoprotein Metabolism, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7270-3176","authenticated-orcid":false,"given":"Stephen G.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California","place":["Los Angeles"]},{"name":"Department of Human Genetics, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-0542","authenticated-orcid":false,"given":"Robert J.","family":"Konrad","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories, Eli Lilly and Company","place":["Indianapolis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7149-316X","authenticated-orcid":false,"given":"Thomas J. D.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark","place":["Odense M, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2215-4265","authenticated-orcid":false,"given":"Michael","family":"Ploug","sequence":"additional","affiliation":[{"name":"Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet","place":["Copenhagen N, Denmark"]},{"name":"Finsen Laboratory, Biotechnology Research and Innovation Centre, University of Copenhagen","place":["Copenhagen N, 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Kumari Data for \u201cANGPTL3\/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase as measured by hydrogen\/deuterium exchange mass spectrometry (HDX-MS).\u201d PRIDE Database. http:\/\/proteomecentral.proteomexchange.org\/cgi\/GetDataset?ID=PXD060125. Deposited 23 January 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2420721122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T18:26:59Z","timestamp":1742495219000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2420721122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,20]]},"references-count":55,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,3,25]]}},"alternative-id":["10.1073\/pnas.2420721122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2420721122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,20]]},"assertion":[{"value":"2024-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2420721122"}}