HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo

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dc.authoridBurçin Güngör / 0000-0001-7725-5835
dc.authorscopusidBurçin Güngör / 54583544500
dc.authorwosidBurçin Güngör / AAF-6654-2021
dc.contributor.authorGüngör, Burçin
dc.contributor.authorVanharanta, Lauri
dc.contributor.authorHoltta-Vuori, Maarit
dc.contributor.authorPirhonen, Juho
dc.contributor.authorPetersen, Nikolaj H. T.
dc.contributor.authorGramolelli, Silvia
dc.contributor.authorIkonen, Elina
dc.date.accessioned2020-08-30T20:06:33Z
dc.date.available2020-08-30T20:06:33Z
dc.date.issued2019
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümüen_US
dc.description.abstractObjective: Heat Shock Proteins (HSPs) maintain cellular homeostasis under stress. HSP70 represents a major stress-inducible family member and has been identified as a druggable target in inherited cholesterol-sphingolipid storage diseases. We investigated if HSP70 modulates cholesterol accumulation in more common conditions related to atherogenesis. Methods: We studied the effects of recombinant HSP70 in cholesterol-laden primary macrophages from human blood donors and pharmacological HSP70 upregulation in high-cholesterol diet fed zebrafish. Results: Recombinant HSP70 facilitated cholesterol removal from primary human macrophage foam cells. RNA sequencing revealed that HSP70 induced a robust transcriptional re-programming, including upregulation of key targets of liver X receptors (LXR), master regulators of whole-body cholesterol removal. Mechanistically, HSP70 interacted with the macrophage LXRalpha promoter, increased LXRalpha and its target mRNAs, and led to elevated levels of key proteins facilitating cholesterol efflux, including ATP-binding cassette transporters A1 and G1. Pharmacological augmentation of endogenous HSP70 in high-cholesterol diet fed zebrafish activated LXR and its target mRNAs and reduced cholesterol storage at the whole organism level. Conclusion: These data demonstrate that HSP70 exerts a cholesterol lowering effect in primary human cells and animals and uncover a nuclear action of HSP70 in mediating cross-talk between HSP and LXR transcriptional regulation. (C) 2019 The Authors. Published by Elsevier GmbH.en_US
dc.description.sponsorshipUniversity of Helsinki; Academy of FinlandAcademy of Finland [282192, 284667, 307415, 307366, 309544]; Orphazyme A/S; Sigrid Juselius FoundationSigrid Juselius Foundationen_US
dc.description.sponsorshipWe thank Anna Uro and Pipsa Kaipainen for technical assistance and HiLIFE infrastructures (Biomedicum Imaging Unit, Zebrafish Unit, Functional Genomics Unit). This study was financially supported by the University of Helsinki, Academy of Finland (grants 282192, 284667, 307415 to E.I.; 307366 to P.M.O. and 309544 to S.G.), Orphazyme A/S, and Sigrid Juselius Foundation (grant to E.I.).en_US
dc.identifier.citationGungor, B., Vanharanta, L., Holtta-Vuori, M., Pirhonen, J., Petersen, N. H. T., Gramolelli, S., … Ikonen, E. (2019). HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo. MOLECULAR METABOLISM, 28, 135–143. https://doi.org/10.1016/j.molmet.2019.07.005en_US
dc.identifier.doi10.1016/j.molmet.2019.07.005en_US
dc.identifier.endpage143en_US
dc.identifier.issn2212-8778en_US
dc.identifier.pmid31327756en_US
dc.identifier.startpage135en_US
dc.identifier.urihttps://doi.org/10.1016/j.molmet.2019.07.005
dc.identifier.urihttps://hdl.handle.net/20.500.12713/554
dc.identifier.volume28en_US
dc.identifier.wosWOS:000487684000012en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakPubMeden_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.institutionauthorGüngör, Burçinen_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.ispartofMolecular Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectCholesterol Metabolismen_US
dc.subjectLiver X Receptoren_US
dc.subjectHeat Shock Proteinen_US
dc.subjectHuman Macrophagesen_US
dc.subjectTranscriptional Regulationen_US
dc.titleHSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivoen_US
dc.typeArticleen_US

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