Intracellular CIRP promotes liver regeneration while extracellular CIRP induces ER stress after partial hepatectomy in mice

Abstract

Abstract Background Cold-inducible RNA-binding protein (CIRP) is a cold shock protein implicated in the regulation of multiple biological processes depending on its cellular localization. However, its role in liver regeneration and injury after hepatectomy has not been investigated. This study was therefore designed to explore whether CIRP was involved in liver regeneration after hepatectomy and its specific role and underlying molecular mechanism. Methods Male adult mice were subjected to two-thirds partial hepatectomy. Hepatic and serum levels of CIRP were measured after hepatectomy. The overall involvement of CIRP in liver regeneration and injury after hepatectomy was evaluated in CIRP-deficient mice. C23, an antagonist of extracellular CIRP, was used to assess the effect of extracellular CIRP on liver regeneration and injury after hepatectomy. CIRP overexpression and shRNA plasmids were transfected to HepG2 cells to study the effect of intracellular CIRP on cell proliferation. The effect of extracellular CIRP on cell proliferation and injury was determined using recombinant CIRP protein to stimulate HepG2 cells in vitro. Results Both hepatic and serum CIRP levels were significantly increased after partial hepatectomy. CIRP deficiency impaired liver regeneration, while alleviated liver injury after partial hepatectomy in mice. C23 administration attenuated liver injury, suppressed ER stress and oxidative stress. However, it had no effects on liver regeneration after partial hepatectomy. Loss- and gain-of-function analyses in hepG2 cells indicated that upregulation of intracellular CIRP promoted cell proliferation via activation of the STAT3 signaling pathway. On the other hand, recombinant CIRP had no effects on cell proliferation and STAT3 phosphorylation, but induced ER stress via a TLR4-dependent pathway in hepG2 cells. Conclusion Taken together, our results demonstrated that intracellular CIRP promotes liver regeneration by activating the STAT3 pathway, while extracellular CIRP induces ER stress via interacting with TLR4 after hepatectomy.