TY - JOUR
T1 - Factor VII activating protease (FSAP) exerts anti-inflammatory and anti-fibrotic effects in liver fibrosis in mice and men
AU - Borkham-Kamphorst, Erawan
AU - Zimmermann, Henning W.
AU - Gassler, Nikolaus
AU - Bissels, Ute
AU - Bosio, Andreas
AU - Tacke, Frank
AU - Weiskirchen, Ralf
AU - Kanse, Sandip M.
N1 - Funding Information:
This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Bonn, Germany) to SMK (Ka 1468/4-1) as well as Behring Röntgen Stiftung and the Excellence Cluster in Cardiopulmonary Medicine (ECCPS). RW and FT are supported by the Deutsche Forschungsgemeinschaft (SFB/TRR57, Ta434/2-1). RW is further funded by the IZKF Aachen. The authors have no conflicting financial interests and nothing to declare.
PY - 2013/1
Y1 - 2013/1
N2 - Background & Aims: Factor VII activating protease (FSAP) is a circulating serine protease produced in the liver. A single nucleotide polymorphism (G534E, Marburg I, MI-SNP) in the gene encoding FSAP (HABP2) leads to lower enzymatic activity and is associated with enhanced liver fibrosis in humans. FSAP is activated by damaged cells and its substrates include growth factors and hemostasis proteins. Methods: We have investigated the progression of liver fibrosis in FSAP deficient mice and FSAP expression in human liver fibrosis. Results: Serum FSAP concentrations declined in patients with end-stage liver disease, and hepatic FSAP expression was decreased in patients with advanced liver fibrosis and liver inflammation. Moreover, there was an inverse correlation between hepatic FSAP expression and inflammatory chemokines, chemokine receptors as well as pro-fibrotic mediators. Upon experimental bile duct ligation, FSAP-/- mice showed enhanced liver fibrosis in comparison to wild type mice, alongside increased expression of α-smooth muscle actin, collagen type I and fibronectin that are markers of stellate cell activation. Microarray analyses indicated that FSAP modulates inflammatory pathways. Conclusions: Lower FSAP expression is associated with enhanced liver fibrosis and inflammation in patients with chronic hepatic disorders and murine experimental liver injury. This strengthens the concept that FSAP is a "protective factor" in liver fibrosis and explains why carriers of the Marburg I SNP have more pronounced liver fibrosis.
AB - Background & Aims: Factor VII activating protease (FSAP) is a circulating serine protease produced in the liver. A single nucleotide polymorphism (G534E, Marburg I, MI-SNP) in the gene encoding FSAP (HABP2) leads to lower enzymatic activity and is associated with enhanced liver fibrosis in humans. FSAP is activated by damaged cells and its substrates include growth factors and hemostasis proteins. Methods: We have investigated the progression of liver fibrosis in FSAP deficient mice and FSAP expression in human liver fibrosis. Results: Serum FSAP concentrations declined in patients with end-stage liver disease, and hepatic FSAP expression was decreased in patients with advanced liver fibrosis and liver inflammation. Moreover, there was an inverse correlation between hepatic FSAP expression and inflammatory chemokines, chemokine receptors as well as pro-fibrotic mediators. Upon experimental bile duct ligation, FSAP-/- mice showed enhanced liver fibrosis in comparison to wild type mice, alongside increased expression of α-smooth muscle actin, collagen type I and fibronectin that are markers of stellate cell activation. Microarray analyses indicated that FSAP modulates inflammatory pathways. Conclusions: Lower FSAP expression is associated with enhanced liver fibrosis and inflammation in patients with chronic hepatic disorders and murine experimental liver injury. This strengthens the concept that FSAP is a "protective factor" in liver fibrosis and explains why carriers of the Marburg I SNP have more pronounced liver fibrosis.
KW - HABP2
KW - Liver fibrosis
KW - Marburg I SNP
UR - https://www.scopus.com/pages/publications/84871249419
U2 - 10.1016/j.jhep.2012.09.007
DO - 10.1016/j.jhep.2012.09.007
M3 - Article
C2 - 22989567
AN - SCOPUS:84871249419
SN - 0168-8278
VL - 58
SP - 104
EP - 111
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
ER -