ADAM10/17-Dependent Release of Soluble c-Met Correlates with Hepatocellular Damage (c-Met/HGF/shedding/ADAMmetalloproteinase/liver/cholangitis)

The signalling pathway elicited by hepato- cyte growth factor (HGF) and its receptor c-Met is indispensable for liver development and regenera- tion. It has been described that c-Met is released from the cell surface by a disintegrin and metallo- protease 10 (ADAM10) resulting in a soluble c-Met form known as sMet. Using the human hepatocellu- lar HepG2 and hepatic stellate cell LX2 lines we show that sMet is released from the cell surface of liver cells by both ADAM17 and ADAM10, with ADAM17 appearing to be the major proteinase. Moreover, using a mouse model of 3,5-diethoxycar- bonyl-1,4-dihydroxycollidine (DDC)-in du ced hepa- tobiliary obstruction we show that serum levels of sMet correlate well with the liver damage state and consecutive regeneration as well as with established markers of liver damage such as alanine aminotrans- ferase (ALT), aspartate transaminase (AST), alka- line phosphatase (ALP), and total bilirubin. However, sMet exhibited remarkably better correlation with liver damage and inflammation than did serum tu- mour necrosis factor α (TNF-α), whose shedding is also mediated by ADAM proteolytic acti vity. Our re- sults indicate that the proteolytic activity of ADAM10/17 is essential for regulating HGF/c-Met signalling during acute liver damage and following regeneration and that the differential serum levels of sMet together with expression of c-Met/HGF might be a useful indicator not only for damage, but also for ongoing liver regeneration.