Smooth Muscle a-actin Deficiency Leads to Decreased Liver Fibrosis via Impaired Cytoskeletal Signaling in Hepatic Stellate Cells

In the liver, smooth muscle a-actin (SM a-actin) is up-regulated in hepatic stellate cells (HSCs) as they transition to myofibroblasts during liver injury and the wound healing response. Whether SM a-actin has specific functional effects on cellular effectors of fibrosis such as HSC is controversial. Here, the relationship between SM a-actin and type 1 collagen expression (COL1A1), a major extracellular matrix protein important in liver fibrosis, is investigated with the results demonstrating that knockout of SM a-actin leads to reduced liver fibrosis and COL1 expression. The mechanism for the reduction in fibrogenesis in vivo is multifactorial, including not only a reduction in the number of HSCs, but also an HSC-specific reduction in COL1 expression in Acta2-deficient HSCs. Despite a compensatory increase in expression of cytoplasmic ß-actin and ¿-actin isoforms in Acta2-/- HSCs, defects were identified in each transforming growth factor beta/Smad2/3 and ET-1/Erk1/2 signaling in Acta2-/- HSCs. These data not only suggest a molecular link between the SM a-actin cytoskeleton and classic fibrogenic signaling cascades, but also emphasize the relationship between SM a-actin and fibrogenesis in hepatic myofibroblasts in vivo.