HIF Biology
Virtually all tissues require a sufficient supply of oxygen for survival. As a consequence, lack of oxygen triggers a series of emergency protective responses. These responses comprise a highly evolved system of protective biology and physiology present in all aerobic organisms.
Hypoxia is defined as below-normal levels of oxygen in blood or tissue. Hypoxia leads to cellular dysfunction and, if sustained, cell death. Hypoxia can result from a specific event, or can be induced by external or internal conditions leading to pathophysiologies, such as:
- Anemic hypoxia: a decreased concentration of hemoglobin (a protein found in red blood cells which transports oxygen throughout the body) or insufficient number of red blood cells
- Hypoxic hypoxia: insufficient oxygenation of blood in the lungs, such as occurs in certain pulmonary disorders
- Ischemic hypoxia: insufficient oxygen delivery to tissues due to slow or impaired peripheral circulation, as a result of injury or obstruction, such as might occur acutely (e.g., post-myocardial infarction or stroke) or chronically (e.g., chronic heart failure)
A key regulatory component of the body's hypoxia response system is hypoxia-inducible factor (HIF). HIF is a transcription factor that interacts with DNA and regulates the expression of genes whose protein products are involved in a wide range of protective responses to hypoxia. These responses occur at the systemic level, such as erythropoiesis and angiogenesis, and at the cellular level, such as alterations in metabolism that promote cell survival despite oxygen deprivation (cytoprotection).
FibroGen is developing small molecules that selectively modulate the activity of HIF to treat a wide range of diseases. Read more about HIF prolyl hydroxylase inhibitor (HIF-PHI) therapy.
The cellular oxygen-sensing system is critical to the body’s defense against hypoxia by triggering a coordinated set of protective cellular and physiological responses when oxygen levels fall too low. The system has three main protein components: hypoxia-inducible factor (HIF), HIF prolyl hydroxylases (HIF-PHs); and von Hippel-Lindau tumor-suppressor (VHL). In hypoxic conditions, the transcription factor HIF (comprised of two protein subunits HIF-α and HIF-β), binds specific sequences of DNA (hypoxia response elements), leading to activation of certain genes and the proteins they encode. These proteins play important roles in the body’s hypoxic response. HIF is constantly made in virtually all cells, and its activity is controlled by HIF-PH enzymes. When cellular oxygen concentration is normal, HIF-PHs catalyze an oxygen-dependent chemical reaction that adds a hydroxyl group (-OH) to two specific proline (pro) amino acid residues within HIF. Hydroxylated HIF is recognized by VHL, and this interaction leads to polyubiquitinylation (Ub) and subsequent degradation of HIF by the proteasome. FibroGen is engaged in the discovery and development of small molecule drugs that stabilize HIF through inhibition of HIF-PH and selectively activate cellular and physiological responses desired for treating a variety of diseases.
