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.

• Authors: Burcin Gungor, Lauri Vanharanta, Maarit Hölttä-Vuori, Juho Pirhonen, Nikolaj H T Petersen, Silvia Gramolelli, Päivi M Ojala, Thomas Kirkegaard, Elina Ikonen
• Journal: Molecular metabolism (Mol Metab) Vol. 28 Pg. 135-143 (10 2019) ISSN: 2212-8778 [Electronic] Germany
• PMID: 31327756 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.

Chemical References

• HSP70 Heat-Shock Proteins
• Liver X Receptors
• Recombinant Proteins
• Cholesterol

Topics

• Animals
• Cholesterol (administration & dosage, metabolism)
• Diet
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Leukocytes, Mononuclear (metabolism)
• Liver X Receptors (metabolism)
• Macrophages (metabolism)
• Recombinant Proteins (metabolism)
• Zebrafish