Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis

Abstract

Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.

Keywords: chronic liver diseases; hypoxia; hypoxia-inducible factors; liver fibrogenesis; liver fibrosis.

Figure 1

HIFs regulation under normoxic or hypoxic conditions and the hypoxic response. In normoxic conditions, the transcriptional action of heterodimeric hypoxia-inducible factors (HIFs) is prevented by changes introduced into the HIF-α subunit (here HIF-1α is shown) by the action of either prolyl hydroxylases (PHD) or factor inhibiting HIF1 (FIH1). In particular, following the action of PHD, the modified HIF-1α can be recognized by the von Hippel–Lindau (VHL) E3 ubiquitin ligase complex, poly-ubiquitinated (Ub-ubiquitin) and then degraded by the proteasome. Under hypoxic conditions, PHD and FIH are progressively inhibited in an O₂-dependent manner and the heterodimer HIF-1α/HIF-1β can be phosphorylated and stabilized to then form a transcriptional complex with cAMP-response element binding (CREB)-binding protein (CBP) and histone acetyltransferase p300 (p300/CBP) and bind to hypoxia-responsive elements (HRE) in the promoter or enhancer regions of target genes. More details can be found in the text.

Figure 2

Hypoxia and HIF-induced events in liver fibrogenesis and CLD progression, as mainly focused on progressive NAFLD. Hypoxic conditions can upregulate the transcription of the HIF-dependent target genes potentially in any hepatic cell population. According to the focus on progressive NAFLD (and ALD) and steatohepatitis, hepatocytes react by down modulation of the enzyme and factors involved in lipid oxidation but, at the same time, by favoring an increase in lipid storage and fatty acid (FA) synthesis. Hypoxic hepatocytes also upregulate a number of peptides acting as pro-inflammatory as well as pro-fibrogenic mediators (i.e., through their action on either macrophages or myofibroblasts (MFs), including SerpinB3, histidine-rich glycoprotein (HRGP) and oncostatin M (OSM). Some of these mediators, in addition to vascular endothelial growth factor A (VEGF-A) released by all cells exposed to hypoxia, may also act as pro-angiogenic mediators, with chronic inflammatory responses and persistent activation of fibrogenesis and angiogenesis having a major role in driving CLD progression towards more advanced fibrosis and cirrhosis. More details can be found in the text.

Figure 3

Site of action of drugs, small molecules and other agents acting either as HIFα subunit inhibitors or stabilizers. The site of action is shown in the ideal sequence of events, ranging from the HIFα subunit mRNA to the transcriptional activity of heterodimeric HIFs. Please note that the indicated drugs/small molecules/agents just represent a small selection of those developed in these years. For a more comprehensive list and detailed analysis, please refer to Reference [142].