[Show abstract][Hide abstract] ABSTRACT: Platelet-derived growth factor receptor α (PDGFRα) is an isoform of the PDGFR family of tyrosine kinase receptors involved in cell proliferation, survival, differentiation, and growth. In this review, we highlight the role of PDGFRα and the current evidence of its
expression and activities in liver development, regeneration, and pathology—including fibrosis, cirrhosis, and liver cancer. Studies elucidating PDGFRα signaling in processes ranging from profibrotic signaling, angiogenesis, and oxidative stress to epithelial-to-mesenchymal transition
point toward PDGFRα as a potential therapeutic target in various hepatic pathologies, including hepatic fibrosis and liver cancer. Furthermore, PDGFRα localization and modulation during liver development and regeneration may lend insight into its potential roles in various pathologic
states. We will also briefly discuss some of the current targeted treatments for PDGFRα, including multireceptor tyrosine kinase inhibitors and PDGFRα-specific inhibitors.
[Show abstract][Hide abstract] ABSTRACT: Wnt/β-catenin signaling plays an important role in hepatic homeostasis especially in liver development, regeneration and cancer, and loss of β-catenin signaling is often associated with increased apoptosis. To elucidate how β-catenin may be regulating hepatocyte survival, we investigated the susceptibility of β-catenin conditional knockout mice (KO) and littermate controls (WT) to Fas and TNF-α, two common pathways of hepatocyte apoptosis. While comparable detrimental effects from Fas activation were observed in WT and KO, a paradoxical survival benefit was observed in KO mice challenged with D-galactosamine (GalN)/lipopolysaccharide (LPS). KO showed significantly lower morbidity and liver injury due to early, robust and protracted activation of NF-κB in absence of β-catenin. Enhanced NF-κB activation in KO was contributed by increased basal inflammation and TLR4 expression and lack of p65-β-catenin complex in hepatocytes. β-Catenin-p65 complex in WT livers underwent temporal dissociation allowing for NF-κB activation to regulate hepatocyte survival following TNF-α-induced hepatic injury. Decrease of total β-Catenin protein but not its inactivation induced, while β-catenin stabilization either chemically or due to mutations repressed, p65 activity in hepatomas in a dose-dependent manner. Conclusion: β-Catenin-p65 complex in hepatocytes undergoes dynamic changes during TNFα-induced hepatic injury and plays a critical role in NF-κB activation and cell survival. Modulation of β-catenin levels is a unique mode of regulating NF-κB activity and thus may present novel opportunities in devising therapeutics in specific hepatic injuries. (HEPATOLOGY 2012.).