Ccn Proteins In Liver Injury And Disease

CCN proteins regulate a broad spectrum of cellular functions including adhesion, migration, proliferation and survival. CCN family members are produced by various hepatic cells in response to injury or cellular transformation. Repair or regeneration following drug-induced hepatoxicity or hepatic resection is characterized by enhanced expression of CCN2 via pathways that are downstream of the actions of tumor necrosis factor-alpha and/or transforming growth factor-beta. CCN2 and CCN3 levels are enhanced in primary and metastatic hepatocellular carcinoma, while CCN4 is over-produced in cholan-giocarcimonas. In hepatic fibrosis, CCN2 is produced by all major cell types, often downstream of transforming growth factor-beta. CCN2 stimulates a pro-fibrotic phenotype in hepatic stellate cells, the principal fibrogenic cell type, through its regulation of proliferation, adhesion, migration, proliferation and survival as well as production of alpha-smooth muscle actin or collagen I. Binding of CCN2 to stellate cells occurs via cell surface integrin alpha v beta 3 and low density lipoprotein receptor-related protein, both of which utilize heparan sulfate proteoglycans as a co-receptor. CCN proteins are a novel class of cell regulatory molecules that may represent new therapeutic targets for a variety of liver diseases, especially fibrosis and cirrhosis.