Heat shock protein 70 is required for optimal liver regeneration after partial hepatectomy in mice

Abstract

Liver regeneration is a complex process that restores functional tissue following resection or injury, and is accompanied by transient ATP depletion and metabolic stress in hepatic parenchymal cells. Heat shock protein-70 (Hsp70) functions as a chaperone during periods of cellular stress, and induces expression of several inflammatory cytokines identified as key players during early liver regeneration. We therefore hypothesized that Hsp70 would be required in the initiation of regeneration. Investigations were carried out in a 70% partial-hepatectomy (PHx) mouse model with mice lacking inducible Hsp70 (Hsp70−/−). Liver regeneration was assessed post-operatively using the ratio of liver weight to body weight (LW/BW), and sera and tissues were collected for analysis. In addition, gene expression of Hsp related genes were assessed in a cohort of 23 human living-donor liver transplantation donors. In mice, the absence of Hsp70 was associated with reduced postoperative LW/BW, Ki-67 staining, and TNF-α expression compared to wild-type mice. TNF-α expression was also reduced in livers from Hsp70−/− mice following induction with LPS (1 mg/kg). Clinically, the transcription of multiple Hsp genes was upregulated following donor hepatectomy, especially Hsp70 family members. Together, these results suggest that the early phase of successful liver regeneration requires the presence of Hsp70 to induce TNF-α. Further studies are required to determine whether Hsp70 contributes to liver regeneration as a chaperone, by stabilizing specific interactions required for growth signalling, or as a paracrine inflammatory signal, as can occur in models of shock.

Heat Stress Induces Extended Plateau of Hsp70 Accumulation – A Possible Cytoprotection Mechanism in Hepatic Cells

“…A large body of evidence shows that the process of liver regeneration can benefit from hepatic preconditioning, which seems to involve a genetic responsetriggering of HSP expression [Pirkkala et al, 2001]. Recent evidence obtained in Hsp70 -/mice undergoing partial hepatectomy points to a fundamental role of HSP70 in the early stages of liver regeneration [Wolf et al, 2014], and supports earlier findings of low Hsp70 expression levels as a marker of acute rejection in human liver transplantation [Flohe et al, 1998].…”

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“…It was found that extracellular Hsp70 can stimulate innate immune mechanisms by promoting the expression of tumor necrosis factor α and interleukin-6 and downstream nuclear factor kappa B signaling, all of which are biologically important components of early liver regeneration as reported by Joshua et al 29 .…”

Endogenous Interleukin 18 Suppresses Liver Regeneration After Hepatectomy in Mice

“…It also enhances liver regeneration through the reduced production of IFNγ and TNF‐α . In addition, dendritic cells as well as eosinophils are proved to regulate liver regeneration …”

“…(28) In addition, dendritic cells as well as eosinophils are proved to regulate liver regeneration. (29,30) However, little is known whether IL18 serves as a mediator of these immune cells in regulating liver regeneration and also in the corresponding signal pathway. It is reported that IL18 modulates liver inflammation by the recruitment of inflammatory cells, (12) and IL18 transgenic mice have a more prominent liver injury and hepatocyte apoptosis.…”