Abstract
Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) leading to liver dysfunction. Proteomic approaches help to decipher ECM alterations during fibrosis progression. Using a decellularization method, we performed a proteomic analysis of 18 fibrotic human liver samples and identified 106 deregulated ECM proteins. Three members of the fibulin protein family (fibulin-2, -3, and -5) expressed by hepatic stellate cells were significantly associated with fibrosis progression. Integrative analyses of protein-protein interaction networks highlighted different functional annotations for these three fibulins. Gene silencing studies showed that unlike fibulin-2 (FBLN2), fibulin-3 (EFEMP1) depletion impaired focal adhesions, FAK phosphorylation, the fibronectin network, and cell migration. These findings are the first to demonstrate the critical involvement of fibulin-3 in the regulation of hepatic stellate cell focal adhesions and migration, emphasizing the intricate link between chronic liver disease progression and remodeling of the microenvironment.