The role of HMGB1 in liver injury and repair - mechanisms and therapeutic interventionsUniversity of Edinburgh

Liver disease affects millions of people worldwide. The incidence of liver disease in general is rising worldwide. The rate of increase is substantially higher in the UK than other countries in Western Europe. Liver disease constitutes the third commonest cause of premature death in the UK. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost five-fold. Liver disease can result from many triggers; these include diet, alcohol, drugs, viral infection and autoimmune complications. From an economic perspective, the impact of acute and chronic liver disease is substantial. The cost to the NHS for treating paracetamol related acute liver injury is over £60 million/year, for treating alcoholic liver disease the cost is estimated at £2.7 billion/year with the treatment costs in Scotland alone being over £1m per day. For non-alcoholic fatty disease, the cost to the NHS is estimated to be £4.2 billion and will be double that by 2050. Unfortunately, the only curative option for end-stage disease is transplantation. Donor organ availability cannot even meet current demand and many patients die whilst waiting for a suitable organ.

A better understanding of liver disease is required and alternative medical strategies are urgently required for the treatment of advanced liver disease.
The balance of pro and anti-inflammatory pathways represent important 'tipping points' that control either injury repair or development to advanced chronic disease or acute liver failure. Paracetamol overdose and alcoholic liver disease are major medical conditions that result in acute and chronic liver injury respectively. I have previously discovered that a critical inflammatory facilitator, High Mobility Group Box-1 (HMGB1), plays a key role in the progression of these diseases. Furthermore, I have shown that by measuring HMGB1 in the blood of patients, medical doctors and researchers can gain a better understanding of the severity of the disease. This in turn may inform better treatment strategies.

The objective of this project now is to determine the detail of how HMGB1 contributes to the control of acute and chronic liver injury progression or resolution by regulating the communication between different cells within the liver that orchestrate inflammatory responses. I will determine which cell types release HMGB1 and I will characterise the impact that it has on the local environment within the liver. To achieve this I will adopt an approach linking well-characterised and genetically modified animal models of liver disease with novel methods to non-invasively image the diseased or regenerating organ. This project has a clear pathway to help patients and manage acute and chronic liver disease. This will be achieved by developing improved understanding of HMGB1 as a diagnostic tool and through the further development of novel medicines targeting HMGB1 itself.

Liver disease is a major medical problem. Activation of inflammation serves to promote tissue repair but can contribute to injury exacerbation. Understanding mechanisms whereby key danger signals act as master regulators that drive pathological events or promote injury resolution is critical for developing novel therapies and biomarkers of disease status. Recognition of endogenous molecules as danger signals released by cells upon infection or injury is an emerging concept in Hepatology. My previous research has discovered that one such molecule, High Mobility Group Box-1 (HMGB1), is a biomarker of acute and chronic liver injury and key driver linking cell death to sterile inflammation. Extracellular HMGB1 function is controlled by post-translational modifications. However, its precise regulatory role in liver disease has not been investigated, nor has its therapeutic potential been fully elucidated.

This fellowship seeks to dissect the mechanistic role of HMGB1 in the progression and restoration of liver injury and to test novel strategies for its pharmacological modulation. I will test the hypothesis that during liver injury, defined cell types increase the expression of, post-translationally modify and secrete specific HMGB1 isoforms. These isoforms then act as regulatory autocrine and paracrine alarm signals that trigger and/or sustain necrosis and inflammation. To achieve this goal I will utilise novel, cell specific, conditional knock out and transduction models in a loss and gain of function approach. These findings will be reinforced with targeted studies investigating mechanisms by which HMGB1 isoforms regulate parenchymal/non-parenchymal cell cross-talk. Finally, I will determine the utility of anti-HMGB1 biologic therapy in clinically relevant models of liver disease. I will optimise its use through measuring circulating HMGB1 itself and by a novel, real time and non-invasive, HMGB1 hepatic expression reporter in a combined and stratified approach.

Liver disease is a major medical problem worldwide. It is the 5th commonest cause of death in the UK and deaths from liver disease are rapidly rising year on year. Twice as many people now die from liver disease as in 1991 and it kills more people than diabetes and road deaths combined. In the UK, over 800,000 hospital admissions are directly related and attributed to alcohol each year. Over 90,000 people are treated on an annual basis for paracetamol related acute liver injury in England alone. From an economic perspective, the impact of acute and chronic liver disease is substantial. The cost to the NHS for treating paracetamol related acute liver injury is over £60 million/year, for treating alcoholic liver disease the cost is estimated at £2.7 billion/year with the treatment costs in Scotland alone being over £1m per day. For non-alcoholic fatty disease, the cost to the NHS is estimated to be £4.2 billion and will be double that by 2050.

Who might benefit from this research?

1. Key academic beneficiaries include researcher working within basic and clinical Hepatology, Pharmacology and Immunology.
2. Diagnostic sector
3. Pharmaceutical industry
4. Drug regulation
5. Patients (initially liver disease but wider inflammatory conditions later)

How might they benefit from this research?

Currently the only curative option for end-stage liver disease is liver transplantation. Donor organ availability cannot even meet current demand and many patients die whilst waiting for a suitable organ. Alternative therapeutic strategies are urgently required for the treatment of advanced liver disease. Ultimately we are aiming at patients being the main beneficiaries of the impact of this proposal through the further validation of targets and important pathways of disease. Moreover, we further aim to develop new therapies and mechanisms to stratify patients for suitable therapy which has significant potential to impact on the management and treatment of this patient population. Academic researchers will benefit from the discovery of new mechanisms to further understand clinically relevant diseases and to exploit pharmacologically. This community will also benefit from the availability of new reagents and novel animal models of liver disease and inflammation. Further details are also listed in the academic beneficiaries section. New assays and targets will also benefit the diagnostics sector. The pharmaceutical industry will also benefit from developing anti-HMGB1 therapy and also the use of HMGB1 as a biomarker for monitoring disease status and drug toxicity.