title: Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.
abstract: Fibrogenic progression of chronic liver diseases (CLDs) towards the end-point of cirrhosis is currently regarded, whatever the aetiology, as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrogenesis (i.e., the process) is sustained by hepatic populations of highly proliferative, pro-fibrogenic and contractile myofibroblast-like cells (MFs) that mainly originate from hepatic stellate cells (HSC) or, to a less extent, from portal fibroblasts or bone marrow-derived cells. As is well known, liver fibrosis (i.e., the result) is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of extracellular matrix (ECM) components. In this scenario, hypoxic areas represent a very common and major feature of fibrotic and cirrhotic liver during the progression of CLDs. Cells exposed to hypoxia respond by means of heterodimeric hypoxia-inducible factors (HIFs) that translocate into the nucleus and binds to a specific core sequence defined hypoxia-responsive element (HRE), present in the promoter on several genes which are considered as hypoxia-regulated target genes. HIFs transcription factors can activate a complex genetic program designed to sustain several changes necessary to efficiently counteract the decrease in oxygen tension. Accordingly, hypoxia, through up-regulation of angiogenesis, is currently believed to significantly contribute to fibrogenic progression of CLDs, mostly by affecting the pro-fibrogenic and pro-angiogenic behaviour of hepatic MFs. In addition, experimental and clinical evidence generated in the last decade also indicates that angiogenesis and fibrogenesis in CLDs may also be sustained by HIF-dependent but hypoxia-independent mediators.
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cannito
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Paternostro
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Busletta
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bocca
authors.affiliation: Department of Oncology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Colombatto
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Miglietta
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Novo
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, and Interuniversity Centre of Hepatic Pathophysiology, University of Torino, Torino, Italy. maurizio.parola@unito.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002908:Chronic Disease; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology*; D058628:Myofibroblasts / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C116973:HIF3A protein, human