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

MARIE-THERESE SIMON, ALAIN PAULOIN^*, GUILLAUME NORMAND, HANH-TU LIEU, HELENE MOULY, GERARD PIVERT, FRANÇOISE CARNOT, J. GUILHERME TRALHAO, CHRISTIAN BRECHOT and LAURENCE CHRISTA¹

Institut National de la Santé et de la Recherche Médicale U-370, Institutes Necker-Pasteur, Université Paris V, 75742 Paris Cedex 15, France;
^* Biologie Cellulaire et Moléculaire, Institut National de la Recherche Agronomique, Jouy-en-Josas, France;
Service d’Anatomo-pathologie, Hôpital Necker-Enfants Malades, Paris, France; and
Service d’Anatomo-pathologie, Hôpital Européen Georges Pompidou, Paris, France

¹Correspondence: Institut National de la Santé et de la Recherche Médicale U-370, Necker-Pasteur Institutes, Universite Paris V, 156 rue de Vaugirard, 75742 Paris Cedex 15, France. E-mail: christa{at}necker.fr

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- plus actinomycin-D-induced apoptosis. HIP/PAP anti-apoptotic effects against TNF- 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.—Simon, M.-T., Pauloin, A., Normand, G., Lieu, H.-T., Mouly, H., Pivert, G., Carnot, F., Tralhao, J. G., Bréchot, C., Christa, L. HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the PKA signaling pathway.

Key Words: HIP/PAP/Reg-2 • C-type lectin • TNF- • PKA

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