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
Citation
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. 28:135-143.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping