ADAM10/17-dependent release of soluble c-Met correlates with hepatocellular damage

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• The hepatocyte growth factor (HGF)/c-Met pathway is crucial for liver development and regeneration.
• Soluble c-Met (sMet) is generated by ectodomain shedding of c-Met, primarily attributed to ADAM10.
• The precise mechanisms regulating sMet release in liver injury and regeneration require further elucidation.

Purpose of the Study:

• To investigate the roles of ADAM10 and ADAM17 in sMet shedding from liver cells.
• To evaluate the correlation of serum sMet levels with liver damage and regeneration markers in vivo.
• To compare the diagnostic potential of sMet with established liver injury markers and TNF-α.

Main Methods:

• Utilized human hepatocellular HepG2 and hepatic stellate LX2 cell lines to study sMet release.
• Employed a mouse model of 3,5-diethoxycarbonyl-1,4-dihydroxycollidine (DDC)-induced hepatobiliary obstruction.
• Measured serum levels of sMet, ALT, AST, ALP, total bilirubin, and TNF-α.

Main Results:

• Both ADAM10 and ADAM17 contribute to sMet shedding from liver cells, with ADAM17 being the predominant protease.
• Serum sMet levels strongly correlated with the extent of liver damage and regeneration following DDC-induced injury.
• sMet demonstrated a superior correlation with liver damage and inflammation compared to ALT, AST, ALP, total bilirubin, and TNF-α.

Conclusions:

• ADAM10 and ADAM17 activity is essential for regulating HGF/c-Met signaling during acute liver injury and regeneration.
• Serum sMet levels, alongside c-Met and HGF expression, represent a promising biomarker for assessing both liver damage and ongoing regeneration.