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Liver injury leads to fibrosis and cirrhosis. The primary mechanism underlying the fibrogenic response is the activation of hepatic stellate cells (HSCs) which are “quiescent” in normal liver but become “activated” after injury by transdifferentiating into extracellular matrix (ECM) secreting myofibroblasts. Since integrins are important in HSC activation and fibrogenesis, we hypothesized that paxillin, a key downstream effector in integrin signaling may be critical in the fibrosis pathway. Using a cell-culture based model of HSC activation and in vivo models of liver injury, we found that paxillin is upregulated in activated HSCs and fibrotic livers. Overexpression of paxillin (both in vitro and in vivo) led to increased ECM protein expression, and depletion of paxillin in a novel conditional mouse injury model reduced fibrosis. The mechanism of paxillin's effect appeared to be through the actin cytoskeleton, which signals to the ERK pathway and ECM proteins production. The data highlight a novel role for paxillin in HSC biology and fibrosis.
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