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

• Published in: Hepatology (Baltimore, Md.) Vol. 42; no. 3; pp. 618 - 626
• Main Authors: LIEU, Hanh-Tu, BATTEUX, Frédéric, BRECHOT, Christian, CHRISTA, Laurence, SIMON, Marie-Thérèse, CORTES, Alexandre, NICCO, Carole, ZAVALA, Flora, PAULOIN, Alain, TRALHAO, José Guilherme, SOUBRANE, Olivier, WEILL, Bernard
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.09.2005; Wiley-Blackwell
• Subjects: Acetaminophen - antagonists & inhibitors; Acetaminophen - toxicity; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - pharmacology; Antigens, Neoplasm - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - pharmacology; Biomarkers, Tumor - therapeutic use; Computer Science; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Lectins, C-Type - genetics; Lectins, C-Type - therapeutic use; Life Sciences; Liver - cytology; Liver - drug effects; Liver - physiology; Liver Regeneration - drug effects; Liver Regeneration - physiology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Transgenic; Mitochondria, Liver - drug effects; Mitochondria, Liver - pathology; Other diseases. Semiology; Oxidoreductases - metabolism; Pancreatitis-Associated Proteins; Tumors; Immunopathology; Severe combined immunodeficiency; Antimigrainous agent; Liver; Overdosing; Rodentia; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Hip; Necrosis; Hepatitis; Regeneration; Vertebrata; Liver failure; Paracetamol; Mammalia; Analgesic; Mouse; Animal; Antipyretic; Digestive diseases; Pancreas; HIP/PAP
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.20845

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 alpha 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.