HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice

Human hepatocarcinoma‐intestine‐pancreas/pancreatic‐associated protein HIP/PAP is a secreted C‐type lectin belonging to group VII, according to Drickamer's classification. HIP/PAP is overexpressed in liver carcinoma; however, its functional role remains unclear. In this study, we demonstrate that HIP/PAP is a paracrine hepatic growth factor promoting both proliferation and viability of liver cells in vivo . First, a low number of implanted hepatocytes deriving from HIP/PAP‐transgenic mice (<1:1,000) was sufficient to stimulate overall recipient severe combined immunodeficiency liver regeneration after partial hepatectomy. After a single injection of HIP/PAP protein, the percentages of bromodeoxyuridine‐positive nuclei and mitosis were statistically higher than after saline injection, indicating that HIP/PAP acts as a paracrine mitogenic growth factor for the liver. Comparison of the early events posthepatectomy in control and transgenic mice indicated that HIP/PAP accelerates the accumulation/degradation of nuclear phospho–signal transducer activator transcription factor 3 and tumor necrosis factor α level, thus reflecting that HIP/PAP accelerates liver regeneration. Second, we showed that 80% of the HIP/PAP‐transgenic mice versus 25% of the control mice were protected against lethal acetaminophen‐induced fulminate hepatitis. A single injection of recombinant HIP/PAP induced a similar cytoprotective effect, demonstrating the antiapoptotic effect of HIP/PAP. Comparison of Cu/Zn superoxide dismutase activity and glutathione reductase‐like effects in control and transgenic liver mice indicated that HIP/PAP exerts an antioxidant activity and prevents reactive oxygen species‐induced mitochondrial damage by acetaminophen overdose. In conclusion , the present data offer new insights into the biological functions of C‐type lectins. In addition, HIP/PAP is a promising candidate for the prevention and treatment of liver failure. (H EPATOLOGY 2005;42:618–626.)