HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti‐apoptotic functions through the PKA signaling pathway

Abstract

The HIP/PAP (=human Reg-2) C-type lectin encoding gene is activated in primary liver cancers. In normal liver, the protein is undetectable in normal mature hepatocytes and found only in some ductular cells, representing potential hepatic progenitor cells. The aim of this study was to examine the consequences of human HIP/PAP expression in the liver of transgenic mice. We demonstrated that HIP/PAP stimulated liver regeneration after partial hepatectomy. To further investigate the enhanced liver regeneration observed in vivo, primary cultures of hepatocytes were used to evaluate the mitogenic and anti-apoptotic properties of HIP/PAP. HIP/PAP increased hepatocyte DNA synthesis and protected hepatocytes against TNF-alpha plus actinomycin-D-induced apoptosis. HIP/PAP anti-apoptotic effects against TNF-alpha were clearly demonstrated when protein kinase A activity was specifically inhibited by KT5720, and HIP/PAP stimulated PKA-dependent phosphorylation of the proapoptotic Bad protein at Ser-112, suggesting that HIP/PAP may compete with cAMP to stimulate PKA activity. Overall, our results led us to propose a new role for a C-type lectin, HIP/PAP, as a hepatic cytokine that combines mitogenic and anti-apoptotic functions regarding hepatocytes, and consequently acts as a growth factor in vivo to enhance liver regeneration.

Pancreatitis‐Associated Protein Is Related Closely to Neoplastic Proliferative Activity in Patients with Colorectal Carcinoma

“…Many studies have shown correlations between PAP and clinicopathologic parameters and clinical prognosis. Functional studies have indicated that PAP can increase DNA synthesis and acts as a growth factor in vivo to enhance liver generation (Simon et al, 2003). PAP is induced by tumor necrosis factor a, and cells overexpressing PAP show significantly less apoptosis on exposure to tumor necrosis factor a (Malka et al, 2000).…”

Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

“…PAP was considered to play a role as an hepatic cytokine involved in hepatic proliferation and survival and also in liver regeneration (Iovanna et al, 1991;Orelle et al, 1992;Ortiz et al, 1998;Malka et al, 2000;Lieu et al, 2007). PAP also has antibacterial and antiapoptotic properties, which can against pancreatitis and liver injury (Terazono et al, 1988;Simon et al, 2003). Previous studies also revealed the potential role of PAP in the development and regeneration of the central and peripheral nervous system (Livesey et al, 1997;Nishimune et al, 2000).…”

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

“…Two copies of an HSVtk gene cassette (Mc1tk) were added to the end of the left homology arm for negative selection. 31 Linearized targeting vector was electroporated into E14-Tg2a (129/O1a strain) ES cells and the cells selected in G418 and ganciclovir. Resistant clones were picked into 96 well plates for freezing and genomic DNA preparation.…”

“…Two-thirds partial hepatectomy (70%) and overall liver regeneration were evaluated by recovery of liver mass (ratio of liver/body weight expressed as percentage of the initial ratio in quiescent liver), and incorporation of bromodesoxyuridine (BrdU) was performed as previously described. 29 Immunohistochemistry. Immunochemistry was performed using anti-HIP/PAP antibodies as previously described.…”

“…Immunochemistry was performed using anti-HIP/PAP antibodies as previously described. 29 Western Blot Analysis. Western blot analysis from whole regenerative liver and nuclear extracts was performed as previously described.…”