Molecular mechanism of stellate cell activation and therapeutic strategy for liver fibrosis

Excerpt

Hepatic stellate cells, which reside in the space of Disse in close contact with both sinusoidal endothelial cells and hepatocytes, play multiple roles in the pathophysiology of the liver [1]. Quiescent stellate cells represent a principal retinol-storing phenotype and metabolize a small amount of basement membrane-forming substrata such as laminine and type IV collagen. When liver injury occurs, they undergo transformation into myofibroblasts eliciting active proliferation in response to platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor-1 (IGF-1), increased extracellular matrix (ECM) production, increased contractility that is accompanied by the expression of smooth muscle –-actin and the production of endothelin-1 (ET-1), secretion of transforming growth factor-beta (TGF-beta) and monocyte chemotactic protein-1 (MCP-1), retinoid loss, and exhibiting active apoptosis. Stellate cell activation is initiated by oxidative stress of lipid hydroperoxide and reactive aldehyde generated and released by damaged hepatocytes, by paracrine stimulation of PDGF-BB, IGF-1 and TGF-beta derived from activated Kupffer cells, endothelial cells, platelets and infiltrating leukocytes, and by early ECM changes including the production of a splice variant of cellular fibronectin (EIIIA isoform) [2‐5]. Transcriptional activation by a zinc finger gene KLF6, which is induced at the very early stage of liver injury, AP-1 and CCAAT/enhancer binding protein (C/EBP) enhances gene expression regulating ECM accumulation [6]. Activated stellate cells are highly responsive to PDGF-BB and IGF-1 through the induction of receptors for individual growth factors, resulting in the activation of intracellular signal cascade including phosphorylation of tyrosine residues in each growth factor receptor molecule, mitogen activated protein kinase (MAPK), phosphatidil inositol 3-kinase (PI3-K), leading to DNA synthesis and proliferation [7, 8]. TGF-beta is a key regulatory molecule for ECM metabolism and functions as an autocrine and a paracrine mediator. The impact of TGF-beta1 on liver fibrosis has been well documented in a TGF-beta1 knockout mouse model [9], in the remarkable attenuation of the development of liver fibrosis by using soluble type II TGF-beta receptor [10], and in adenoviral delivery of dominant-negative TGF-beta receptor [11]. Role of Smad cascade in TGF-beta signaling has been well characterized. Increased contractility after activation, in particular induced by ET-1, causes constriction of sinusoids, leading to a persistent disturbance of intrahepatic microcirculation and portal hypertension [12, 13]. Thus, analysis of the molecular mechanism underlying stellate cell activation is assumed to be essential for the development of effective therapy against liver fibrosis. …