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 ␣ 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. (HEPATOLOGY 2005;42:618-626.)
C
-type lectins are cation-dependent carbohydratebinding proteins with a common carbohydrate recognition domain of 115-130 amino acid residues. 1 These proteins exhibit various functions such as complement activation, 2 endocytosis, 3 cell recognition, 4 and morphogenesis. 5 It has been recently reported that the viral EP153R protein is endowed with antiapoptotic properties in vitro, which is unexpected for a C-type lectin. 6 The hepatocarcinoma-intestine-pancreas/pancreaticassociated protein (HIP/PAP) is a human 16-kd secreted protein whose complementary DNA has been cloned in humans 7,8 as well as rats, mice, and hamsters under the names PAPI or peptide 23, Reg-2 or RegIII, and IN-GAP, 9 respectively. The HIP/PAP and the lithostatine/ RegI-related genes are classified in group VII of the C-type lectin gene superfamily and encode small secreted proteins with a single carbohydrate recognition domain linked to a signal peptide. 1,10 Because the physiological functions of group VII lectins remain unclear, structurefunction relationships are difficult to establish. The human HIP/PAP protein has been shown to bind lactose, 11