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

Burcin Gungör, Lauri Vanharanta, Maarit Hölttä-Vuori, Juho Pirhonen, Nikolaj H.T. Petersen, Silvia Gramolelli, Päivi M. Ojala, Thomas Kirkegaard, Elina Ikonen

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.
Originalspråkengelska
TidskriftMolecular metabolism
ISSN2212-8778
DOI
StatusPublicerad - 6 jul 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3111 Biomedicinska vetenskaper

Citera det här

@article{f3ca05b994d74128a0586dce19ae4635,
title = "HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo",
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.",
keywords = "Cholesterol metabolism, Liver X receptor, Heat shock protein, Human macrophages, Transcriptional regulation, 3111 Biomedicine",
author = "Burcin Gung{\"o}r and Lauri Vanharanta and Maarit H{\"o}ltt{\"a}-Vuori and Juho Pirhonen and Petersen, {Nikolaj H.T.} and Silvia Gramolelli and Ojala, {P{\"a}ivi M.} and Thomas Kirkegaard and Elina Ikonen",
year = "2019",
month = "7",
day = "6",
doi = "10.1016/j.molmet.2019.07.005",
language = "English",
journal = "Molecular metabolism",
issn = "2212-8778",
publisher = "Elsevier Scientific Publ. Co",

}

HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo. / Gungör, Burcin; Vanharanta, Lauri; Hölttä-Vuori, Maarit; Pirhonen, Juho; Petersen, Nikolaj H.T.; Gramolelli, Silvia; Ojala, Päivi M.; Kirkegaard, Thomas; Ikonen, Elina.

I: Molecular metabolism, 06.07.2019.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo

AU - Gungör, Burcin

AU - Vanharanta, Lauri

AU - Hölttä-Vuori, Maarit

AU - Pirhonen, Juho

AU - Petersen, Nikolaj H.T.

AU - Gramolelli, Silvia

AU - Ojala, Päivi M.

AU - Kirkegaard, Thomas

AU - Ikonen, Elina

PY - 2019/7/6

Y1 - 2019/7/6

N2 - 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.

AB - 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.

KW - Cholesterol metabolism

KW - Liver X receptor

KW - Heat shock protein

KW - Human macrophages

KW - Transcriptional regulation

KW - 3111 Biomedicine

U2 - 10.1016/j.molmet.2019.07.005

DO - 10.1016/j.molmet.2019.07.005

M3 - Article

JO - Molecular metabolism

JF - Molecular metabolism

SN - 2212-8778

ER -