Neuropilins and liver

Neuropilins (NRPs) are highly conserved transmembrane glycoproteins that possess pleiotropic functions. Neuropilin-1 (NRP1) and its homologue neuropilin-2 interact as coreceptors with both class 3 semaphorins and vascular endothelial growth factor and are involved in neuronal guidance and angiogenesis, respectively. The contribution of NRPs to tumor angiogenesis has been highlighted in previous studies, leading to the development of NRP antagonists as novel anti-angiogenesis therapies. However, more recent studies have demonstrated that NRPs have a much broader spectrum of activity in the integration of different pathways in physiological and pathological conditions. A few studies investigated the role of NRPs in both malignant and non-neoplastic liver diseases. In normal liver, NRP1 is expressed in hepatic stellate cells and liver sinusoidal endothelial cells. NRP1 expression in hepatocytes has been associated with malignant transformation and may play an important role in tumor behavior. A contribution of NRPs in sinusoidal remodeling during liver regeneration has been also noted. Studies in chronic liver diseases have indicated that, besides its influence on angiogenesis, NRP1 might contribute to the progression of liver fibrosis owing to its effects on other growth factors, including transforming growth factor β1. As a result, NRP1 has been identified as a promising therapeutic target for future antifibrotic therapies based on the simultaneous blockade of multiple growth factor signaling pathways. In this review, the structure of NRPs and their interactions with various ligands and associated cell surface receptors are described briefly. The current understanding of the roles of the NRPs in liver diseases including tumors, regeneration and fibrogenesis, are also summarized.