PUBLICATION

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

Authors
Gungor, B., Vanharanta, L., Hölttä-Vuori, M., Pirhonen, J., Petersen, N.H.T., Gramolelli, S., Ojala, P.M., Kirkegaard, T., Ikonen, E.
ID
ZDB-PUB-190724-24
Date
2019
Source
Molecular metabolism   28: 135-143 (Journal)
Registered Authors
Keywords
Cholesterol metabolism, Heat shock protein, Human macrophages, Liver X receptor, Transcriptional regulation
MeSH Terms
  • Animals
  • Cholesterol/administration & dosage
  • Cholesterol/metabolism*
  • Diet
  • HSP70 Heat-Shock Proteins/metabolism*
  • Humans
  • Leukocytes, Mononuclear/metabolism
  • Liver X Receptors/metabolism*
  • Macrophages/metabolism
  • Recombinant Proteins/metabolism
  • Zebrafish
PubMed
31327756 Full text @ Mol Metab
Abstract
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.
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.
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.
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping