Pla2g12b drives expansion of triglyceride-rich lipoproteins

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  • dc.contributor.author Thierer, James H.
  • dc.contributor.author Foresti, Ombretta
  • dc.contributor.author Yadav, Pradeep Kumar
  • dc.contributor.author Wilson, Meredith H.
  • dc.contributor.author Moll, Tabea O. C.
  • dc.contributor.author Shen, Meng-Chieh
  • dc.contributor.author Busch-Nentwich, Elisabeth M.
  • dc.contributor.author Morash, Margaret
  • dc.contributor.author Mohlke, Karen L.
  • dc.contributor.author Rawls, John F.
  • dc.contributor.author Malhotra, Vivek
  • dc.contributor.author Hussain, M. Mahmood
  • dc.contributor.author Farber, Steven A.
  • dc.date.accessioned 2024-07-31T12:04:03Z
  • dc.date.available 2024-07-31T12:04:03Z
  • dc.date.issued 2024
  • dc.description.abstract Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear. Here we report that PLA2G12B channels lipids within the lumen of the endoplasmic reticulum into nascent lipoproteins. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium-dependent and tightly associated with the membrane of the endoplasmic reticulum. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.
  • dc.description.sponsorship This work was financially supported by National Institutes of Health grants R01DK093399 (S.A.F., J.F.R), R01HL158054 (S.A.F. and M.M.H.), F31HL149174 (T.O.C.M.), F31HL139338 (J.H.T.), the Mathers Foundation (S.A.F.), the Carnegie Institution for Science endowment (S.A.F.), Ministerio de Economía y Competitividad (RYC-2016-20919, O.F.), Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (PID2019-105518GB-I00, V.M.), and the European Research Council (ERC-2020-SyG-Proposal No. 951146, V.M.).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Thierer JH, Foresti O, Yadav PK, Wilson MH, Moll TOC, Shen MC, et al. Pla2g12b drives expansion of triglyceride-rich lipoproteins. Nat Commun. 2024 Mar 7;15(1):2095. DOI: 10.1038/s41467-024-46102-4
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-46102-4
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/60869
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2024 Mar 7;15(1):2095
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/951146
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-105518GB-I00
  • dc.rights © The Author(s) 2024, corrected publication. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Genetics
  • dc.subject.keyword Lipoproteins
  • dc.subject.keyword Metabolic disorders
  • dc.title Pla2g12b drives expansion of triglyceride-rich lipoproteins
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion