Abstract
Liver cirrhosis (LC) is a disease characterized by pathological accumulation and alteration of extracellular matrix (ECM) proteins; the interaction between two such proteins, collagen and vitronectin (VN), is considered to be the key to controlling ECM remodeling in liver cirrhosis. If it is possible to control the modification of oligosaccharides on VN, it may be possible to retard progression of liver cirrhosis. In this study, we examined the relationship between changes in VN glycosylation and activity related to the remodeling of hepatic tissue in human LC and a rat model of LC generated using carbon tetrachloride (CCl4). Plasma concentrations of VN in human LC declined to approximately two‐thirds that in normal plasma, but the ratio of active VN, which has collagen‐binding activities, increased 2.8 times in LC plasma. In contrast, purified LC‐VN exhibited similar binding activities toward type I, IV, and V collagens to those of normal VN. Lectin reactivities and carbohydrate analyses of LC‐VN revealed that branching, fucosylation, and sialylation of N‐glycans were higher than those of normal VN. On the other hand, the plasma level of rat CCl4‐VN increased and the ratio of active molecules to collagen in plasma decreased. Increased fucosylation of LC‐VN was not detected in carbohydrates of CCl4‐VN. The changes in rat VN due to CCl4 treatment did not correspond to the changes in plasma levels of human VN caused by LC, the ratio of active molecules, or carbohydrate composition, thereby indicating that CCl4‐treated rats are not an appropriate model for studying VNs in human LC. Glycosidase treatment of VNs supported the hypothesis that the collagen‐binding activity of VN is modulated by alterations of glycosylation during LC, which may contribute to (a) the matrix incorporation of VN and (b) tissue fibrosis.
Highlights
Liver cirrhosis (LC) is a disease characterized by pathological accumulation and alteration of extracellular matrix (ECM) proteins; the interaction between two such proteins, collagen and vitronectin (VN), is considered to be the key to controlling ECM remodeling in liver cirrhosis
VN is found in the extracellular matrix (ECM) of most tissues and is considered to play a role in cell adhesion, cell motility, and matrix remodeling; VN is present as an active multimeric form that interacts with various matrix ligands, such as type 1 plasminogen activator inhibitor and urokinase receptor to regulate pericellular proteolysis, various types of integrins on the cell surface, and various types of collagen [2,4,9]
Parallel to the decrease of the total protein concentration in plasma, the VN level in LC plasma decreased to approximately 69% of that in normal plasma (Fig. 1B)
Summary
Liver cirrhosis (LC) is a disease characterized by pathological accumulation and alteration of extracellular matrix (ECM) proteins; the interaction between two such proteins, collagen and vitronectin (VN), is considered to be the key to controlling ECM remodeling in liver cirrhosis. VN regulates the blood systems related to protease cascades such as cell lysis by complement, coagulation, and fibrinolysis [5] Both inactive monomeric and active multimeric forms of VN have been identified in circulating blood [6]. Most VN in normal plasma exists mainly as an inactive monomeric form that scarcely binds to its ligands, but it acquires binding activity to its ligands in a multimeric forms by treatment with denaturants such as urea in vitro [7]. This characteristic is the basis of the VN purification method using heparin-affinity chromatography [8]. Stepwise trimming of N-glycans of VN with various exoglycosidases increases the collagen-binding activity and induces formation of large-sized multimer VNs [15]
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