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 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.
Lieu
Hanh-Tu
HT
Institut National de la Santé et de la Recherche Médicale U-370; Faculté de Médecine, Université Paris 5; Hôpital Necker, Institut Pasteur de Paris, Paris, France.
Batteux
Frédéric
F
Simon
Marie-Thérèse
MT
Cortes
Alexandre
A
Nicco
Carole
C
Zavala
Flora
F
Pauloin
Alain
A
Tralhao
José Guilherme
JG
Soubrane
Olivier
O
Weill
Bernard
B
Bréchot
Christian
C
Christa
Laurence
L
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics* / Q000627:therapeutic use; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D000082:Acetaminophen; D010088:Oxidoreductases; C121849:superoxide reductase