Hypoxia-inducible factors as molecular targets for liver diseases

Abstract

Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease.

Keywords: Alcoholic liver disease; Fatty liver; HIF1α; HIF2α; Hepatocellular carcinoma; Ischemia-reperfusion liver injury; Viral hepatitis.

Fig. 1

Hypoxia-dependent and hypoxia-independent mechanisms responsible for hepatic stabilization of hypoxia-inducible factor HIF. Under normoxic conditions, HIF is hydroxylated via prolyl hydroxylases (PHDs) and thereby target HIF for proteasomal degradation. Hypoxia-dependent and hypoxia-independent pathways can result in PHD inhibition and concomitant HIF stabilization during liver disease. The left side of the figure displays conditions of liver disease that directly lead to a hypoxic microenvironment. During conditions of liver disease, imbalance in supply and demand for metabolites—particularly oxygen—can lead to hepatic hypoxia, including diminished supply with oxygen through the vasculature. Hypoxia-associated increases in reactive oxygen species (ROS) have been reported to lead to PHD inhibition. Similarly, infiltrating inflammatory cells can deplete the microenvironment from oxygen, for example, poly-morphonuclear neutrophils (PMN) undergoing PMN burst [15]. Hypoxia-independent pathways leading to PHD inhibition include activation of toll-like receptors (particularly TLR4) through bacterial products, such as lipopolysaccharide (LPS). Accumulation of the citrate cycle intermediate succinate can function as a PHD inhibitor [181]. Iron depletion of the micro-environment for example through bacterial siderophores can lead to PHD inhibition and HIF stabilization [182]. Moreover, elevated transcription of HIF can be a direct effect during infection with hepatitis B (HBV) or hepatitis C (HCV) virus

Fig. 2

Hypoxia-stimulated adenosine production and signaling during hepatic ischemia and reperfusion injury. During liver transplantation, ischemia and reperfusion injury of the liver graft results in profound hypoxia and concomitant increases in hypoxia-dependent signaling pathways. One of the main outcomes of these transcriptional programs is increased production and signaling of the extracellular signaling molecule adenosine. During liver injury, multiple cell types release nucleotides in the form of adenosine triphosphate (ATP) or adenosine diphosphate (ADP). ATP and ADP are enzymatically converted via CD39 to adenosine monophosphate (AMP), which in turn is converted to adenosine via the enzyme CD73 [49]. Conditions of hepatic hypoxia will result in the transcriptional induction of CD39 via the transcription factor SP1 [45] and of CD73 via the transcription factor hypoxia-inducible factor HIF [47]. Similarly, the A2A and A2B adenosine receptors are transcriptionally induced by HIF [48, 49]. Many studies have implicated increased extracellular adenosine signaling in liver protection from ischemia and reperfusion injury [53]

Fig. 3

Targeting hepatic hypoxia-signaling for the treatment of liver disease. Most evidence points towards a tissue protective role of hypoxia-inducible transcription factors (HIFs) during acute liver injury, while in conditions of chronic liver disease, inhibition of HIFs may be desirable. Pharmacologic approaches to enhance hepatic stabilization of HIFs during liver disease can be achieved by pharmacologic inhibitors of prolyl hydroxylases (PHDs). Such compounds are currently examined in clinical trials and could potentially provide liver protection during acute liver injury. Clinical trials providing direct evidence for this hypothesis have yet to be completed and published. During conditions of chronic liver disease, inhibition of HIF stabilization in the liver may provide a therapeutic benefit. For example, oligo-nucleotide inhibitors for HIF are in clinical trials for the treatment of liver cancer