Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis |
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| Authors: | Maren Ilowski Axel Kleespies Enrico N de Toni Barbara Donabauer Karl-Walter Jauch Jan G Hengstler Wolfgang E Thasler |
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| Institution: | aLiver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany;bDepartment of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany;cDepartment of Medicine II, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany;dLeibniz Research Centre for Working Environment and Human Factors, Technical University, Dortmund, Germany |
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| Abstract: | Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-β, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining.ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines.Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings. |
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| Keywords: | Abbreviations: rhALR recombinant human augmenter of liver regeneration EGF epidermal growth factor ERK-1/2 extracellular signal&ndash regulated kinase 1/2 FCS fetal calf serum HGF hepatocyte growth factor LPS lipopolysaccharide MAP kinase mitogen-activated protein-kinase MAPKK/MEK mitogen-activated protein kinase kinase MTS 3-(4 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium TRAIL tumor necrosis factor related apoptosis-inducing ligand TGF-β transforming growth factor beta act D actinomycin D NEAA non essential amino acids FACS fluorescence activated cell sorting phH primary human hepatocytes |
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