Investigating hepatic p53-mediated neutrophil suppression in non-alcoholic steatohepatitis

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Liver cancer is a common and lethal disease with few treatment options. Rates of liver cancer in Scotland are highest in the UK for both women and men (both approximately 1.5 times higher than average). As a result of the obesity epidemic, the main causes of liver cancer are shifting. Cases were historically associated with viral infection, but this is decreasing. Now, a rising proportion of new cases of liver cancer result from individuals first developing a condition called non-alcoholic steatohepatitis (NASH). Projecting into the future, NASH-derived liver cancer is expected to shortly become the dominant form of liver cancer. Worryingly, obesity and type 2 diabetes-key contributors to developing advanced NASH-are also most common in Scotland within the UK. Moreover, NASH-derived liver cancer can be especially resistant to existing treatment options, suggesting that without urgent action, a bad situation could become a crisis in Scotland and across the UK as NASH-derived liver cancer becomes dominant. The focus of our research will be on a gene called p53, which has long been established as a 'guardian of the genome' and an important defender against the development of cancer. Our preliminary findings suggest that p53 exerts a similarly protective function in the liver in response to consumption of a high fat and high sugar 'western' diet. In this setting, our evidence suggests that p53 protects liver function and acts to oppose the development of diet-induced NASH. For this study, we are particularly interested in understanding the relationship between p53 activity and specific immune cells called neutrophils, which normally infiltrate the liver in response to damage or disease to help facilitate tissue repair. However, in liver disease, undue persistence of neutrophils in the liver can contribute to chronic liver inflammation and has also been shown to promote the development of treatment-resistant liver cancer in human NASH patients. Within this context, targeting neutrophils alongside the administration of cancer therapy can improve treatment efficacy. Our preliminary evidence suggests that p53 may protect the liver, at least in part, by also acting to restrict neutrophil infiltration. With the proposed project, we will determine whether p53-mediated neutrophil suppression is important for protection from NASH. We will also identify periods during liver disease progression where increasing neutrophil activity strongly correlates with disease advancement, suggesting an opportunity for neutrophil-targeted intervention. Using this information, we plan to test whether early intervention targeting neutrophils in liver disease can delay or even prevent the development of NASH-potentially pointing to a new therapeutic approach for a condition (NASH) without any currently approved treatment options. Any such advances would have an outsize impact on patients in Scotland, and future patient-focused work would benefit from the existing infrastructure and established clinical cohorts of patients at-risk of developing liver cancer that are already present there.