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

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 α-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 PDGFRβ 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 “protective factor” 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. Overall design: The dataset comprises 12 samples divided into four sample groups each representing a certain treatment group.

背景与研究依据：因子VII激活蛋白酶（Factor VII activating protease, FSAP）是一种由肝脏合成的循环丝氨酸蛋白酶。编码FSAP的基因（HABP2）存在单核苷酸多态性位点G534E（即马尔堡I型，Marburg I, MI-SNP），该多态性可导致FSAP酶活性降低，并与肝纤维化程度加重显著相关。FSAP可被受损细胞激活，其底物涵盖生长因子与止血相关蛋白。本研究针对FSAP缺陷小鼠的肝纤维化进展展开了探究。

研究结果：将野生型（Wild type, WT）或FSAP敲除（FSAP-/-）小鼠施以胆管结扎（bile duct ligation, BDL）造模，随后评估其肝纤维化程度。天狼星红（Sirius Red）染色与羟脯氨酸含量检测结果显示，FSAP-/-小鼠的肝纤维化程度与细胞外基质沉积量均显著升高。通过肝脏坏死程度与循环肝酶水平评估，FSAP缺陷小鼠的肝损伤更为严重，该表型与肝星状细胞活化标志物（如α-平滑肌肌动蛋白、胶原蛋白、纤连蛋白）的表达上调相一致。FSAP缺陷小鼠体内的血小板衍生生长因子BB（PDGF-BB）及其受体β（PDGFRβ）表达水平更高，而二者均为肝纤维化的强激活因子。为进一步阐明该表型差异的潜在机制，本研究开展了基因芯片（microarray）分析，结果显示野生型与FSAP敲除小鼠的基因表达谱差异提示，FSAP可调控机体炎症与免疫系统。

结论：FSAP敲除小鼠的实验结果与人类中MI-SNP导致FSAP活性降低、肝纤维化加重的临床情况相符，进一步证实FSAP是肝纤维化的“保护因子”。该保护作用的潜在机制可能与FSAP调控肝脏内纤维化与炎症相关进程有关。

整体实验设计：本数据集共包含12个样本，划分为4个样本组，每组对应一种独立的处理方案。