Signaling molecules and pathways involved in HSC activation

A panoply of signals drive hepatic stellate cell (HSC) activation. Key fibrogenic and proliferative pathways contribute to fibrosis, include transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF). Hedgehog (Hh) ligand and its receptor smoothened homolog (SMO) promote HSC activation. G protein-coupled receptors expressed by HSCs can either negatively or positively affect HSC activation. Innate immune signaling, especially that mediated by Toll-like receptors (TLRs) and cytokines, has been implicated in HSC activation. Adipokines mediate crosstalk between liver, adipose and other tissues. Autophagy drives HSC activation by providing energy substrates and is linked to increased endoplasmic reticulum (ER) stress. Oxidative stress is a feature of chronic liver disease that activates HSCs. Loss of retinoid is a defining characteristic of HSC activation. Free cholesterol stimulates HSCs by rendering them susceptible to TGF-beta. Nuclear receptors negatively modulate HSC activation. Epigenetic signals including microRNAs (miRNAs), DNA methylation and histone modification control both activation and inactivation of HSCs.