Proteomic analysis of liver fibrosis reveals EFEMP1 as a new modulator of focal adhesion and migration of hepatic stellate cells

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.