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

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http://hdl.handle.net/10138/306649

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Gungor , B , Vanharanta , L , Hölttä-Vuori , M , Pirhonen , J , Petersen , N H T , Gramolelli , S , Ojala , P M , Kirkegaard , T & Ikonen , E 2019 , ' HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo ' , Molecular metabolism , vol. 28 , pp. 135-143 . https://doi.org/10.1016/j.molmet.2019.07.005

Title: HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo
Author: Gungor, Burcin; Vanharanta, Lauri; Hölttä-Vuori, Maarit; Pirhonen, Juho; Petersen, Nikolaj H. T.; Gramolelli, Silvia; Ojala, Päivi M.; Kirkegaard, Thomas; Ikonen, Elina
Contributor: University of Helsinki, Department of Anatomy
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, University Management
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, University Management
University of Helsinki, Lipid Trafficking Lab
Date: 2019-10
Language: eng
Number of pages: 9
Belongs to series: Molecular metabolism
ISSN: 2212-8778
URI: http://hdl.handle.net/10138/306649
Abstract: Objective: 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.
Subject: Cholesterol metabolism
Liver X receptor
Heat shock protein
Human macrophages
Transcriptional regulation
HEAT-SHOCK-PROTEINS
HEAT-SHOCK-PROTEIN-70
ATHEROSCLEROSIS
MECHANISMS
TRANSPORT
MEMBRANE
EFFLUX
HSP90
3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
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