Unknown,Transcriptomics,Genomics,Proteomics

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Factor VII activating protease (FSAP) exerts antifibrotic effects in a mouse model of experimental liver fibrosis

ABSTRACT: Background and Rationale: 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. FSAP is activated by damaged cells and its substrates include growth factors and haemostasis proteins. We have investigated the progression of liver fibrosis in FSAP deficient mice. Results: Wild type (WT) or FSAP-/- mice were subjected to bile duct ligation (BDL) and assessment of liver fibrosis. FSAP-/- mice showed enhanced liver fibrosis and accumulation of extracellular matrix as determined by Sirius Red staining and hydroxyproline content. FSAP deficient mice exhibited stronger injury as determined by higher necrosis in the liver and circulating liver enzymes. This correlated with expression of markers like M-NM-1-smooth muscle actin, collagen and fibronectin that are markers of stellate cell activation. FSAP-deficient mice exhibited higher expression of PDGF-BB as well as PDGFRM-NM-2 that are strong activators of liver fibrosis. In order to gain more insight into this difference microarray analysis was performed and the pattern of gene expression in WT vs. FSAP-/- mice would indicate that FSAP modulates the inflammatory /immune system. Conclusions: The results with FSAP-/- mice correlates with the human situation where lower FSAP activity, due to the MI SNP, is associated with enhanced liver fibrosis. This strengthens the concept that FSAP is a M-bM-^@M-^\protective factorM-bM-^@M-^] in liver fibrosis. A probable mechanism for this effect is likely to be related to the role of FSAP in the regulation of fibrosis/ inflammation-related processes n the liver. The dataset comprises 12 samples divided into four sample groups each representing a certain treatment group.

ORGANISM(S): Mus musculus

SUBMITTER: Ute Bissels

PROVIDER: E-GEOD-36066 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.

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Factor VII activating protease (FSAP) exerts antifibrotic effects in a mouse model of experimental liver fibrosis

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