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

Liver regeneration is a complex process that restores functional tissue after resection or injury, and it is accompanied by transient adenosine triphosphate depletion and metabolic stress in hepatic parenchymal cells. Heat shock protein 70 (Hsp70) functions as a chaperone during periods of cellular stress and induces the expression of several inflammatory cytokines identified as key players during early liver regeneration. We, therefore, hypothesized that Hsp70 is required for the initiation of regeneration. Investigations were carried out in a 70% partial hepatectomy mouse model with mice lacking inducible Hsp70 (Hsp70(-/-)). Liver regeneration was assessed postoperatively with the liver weight/body weight (LW/BW) ratio, and sera and tissues were collected for analysis. In addition, the expression of Hsp-related genes was assessed in a cohort of 23 human living donor liver transplantation donors. In mice, the absence of Hsp70 was associated with a reduced postoperative LW/BW ratio, Ki-67 staining, and tumor necrosis factor alpha (TNF-alpha) expression in comparison with wild-type mice. TNF-alpha expression was also reduced in livers from Hsp70(-/-) mice after induction with lipopolysaccharide (1 mg/kg). Clinically, the transcription of multiple Hsp genes (especially Hsp70 family members) was up-regulated after donor hepatectomy. Together, these results suggest that the early phase of successful liver regeneration requires the presence of Hsp70 to induce TNF-alpha. Further studies are required to determine whether Hsp70 contributes to liver regeneration as a chaperone by stabilizing specific interactions required for growth signaling or as a paracrine inflammatory signal, as can occur in models of shock. Liver Transpl 20:376-385, 2014. (c) 2013 AASLD.