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

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

Heat shock protein 70 (HSP70) is a chaperone that facilitates protein folding and transport, with essential roles in maintaining cell homeostasis and survival. In addition to its chaperone function in proteostasis, HSP70 can act as a signaling molecule. Gungor, Vanharanta, et al. studied the effects of rHSP70 on human primary monocyte-derived macrophage foam cells that accumulate cholesterol, which leads to artherosclerosis. They found that HSP70 exerts atheroprotective effects and that this can be mechanistically explained by HSP70 mediated stimulation of the liver X receptor, the master regulator of cholesterol removal.

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.

Conclusions: 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.