Fibrogenic signalling in hepatic stellate cells

(1) Upon liver damage, hepatic stellate cells undergo a process defined as activation (Fig. 1), that enables them to acquire a myofibroblastic phenotype. The biological actions of myofibroblasts are pivotal for liver tissue repair and fibrogenesis [1]. (2) Activation of TGFb-dependent fibrogenic signalling in hepatic stellate cells. The source of TGFb is initially paracrine including hepatocytes, Kupffer cells, and platelets activated in response to hepatic injury [2]. (3) At the same time TLR4 signalling in hepatic stellate cells is required for down-regulation of TGFb pseudoreceptor (and inhibitor) BAMBI in order to render hepatic stellate cells sensitive to TGFb signalling. Bacterial-derived LPS is currently considered to be the key fibrogenic TLR4 ligand; however, additional endogenous ligands from damaged and dying hepatocytes cannot yet be ruled out as playing a role [3]. (4) TGFb signals generate transcriptional active pro-fibrogenic Smad2 and Smad3 complexes [2], but also stimulates collagen transcription in hepatic stellate cells via hydrogen peroxide and C/EBPb. (5) Transcription factors Sp1 and KLF6 stimulate TGFb gene transcription in hepatic stellate cells to provide autocrine fibrogenic signalling. (6) Accumulation of fibrillar matrix is facilitated by increased expression of tissue inhibitors of metalloproteinases (TIMPs). (7) Agonists of the nuclear receptor PPARc oppose TGFb signalling by inhibiting activation of hepatic stellate cells and collagen expression. PPARc expression is diminished during activation of hepatic stellate cells by an epigenetic mechanism involving the methylCpG binding protein MeCP2. Ongoing clinical trials with PPARc agonists will determine their efficacy as anti-fibrotics [4]. (8) Kupffer cells and damaged hepatocytes generate reactive oxygen species (ROS) [5] which stimulate hepatic stellate cell expression of chemokines and amplification of inflammation by an NF-jB-dependent pathway. (9) Paracrine and autocrine PDGF signalling [1,5] via PI3 Kinase and ERK serves to perpetuate hepatic stellate cell activa-