Understanding the mechanisms underlying the detrimental effects of NAFLD on the brain

Numerous studies have shown the detrimental effects of an unhealthy lifestyle and obesity on the brain, as well as the association with increased risk for developing other neurological disorders, such as dementia. Non-alcoholic fatty liver disease (NAFLD) is a serious liver disorder, which often coexists with other chronic conditions, contributing to the global health crisis of multimorbidity (defined as multiple chronic diseases occurring in the same person at the same time). NAFLD affects approximately 1 in 5 people worldwide, with the highest prevalence in obese people. It is now becoming clear that NAFLD is affecting other organs including the brain and it is associated with impaired cognitive performance, depressive mood, anxiety, apathy and accelerated ageing of the brain. The brain consumes 20% of oxygen we inspire and 20% of glucose we consume, with both oxygen and metabolic substrates carried to the brain via the blood. Therefore, insufficient blood supply can result in metabolic deficit and eventually cellular damage, leading to cognitive decline and neurodegeneration, as seen in Alzheimer's disease and ageing. In order to maintain appropriate and sufficient energy supply, the brain has an intricate network of blood vessels, which effectively maintain brain metabolic homeostasis by delivering oxygen and nutrients, as well as by ensuring the clearance of metabolic waste products. My research indicated that NAFLD is associated with decreases in the density of blood vessels in the brain, which lead to a reduced oxygen supply. This alone could be responsible for the cognitive and behavioural alterations, as well as the increased risk of dementia reported in patients with NAFLD. However, the search for neuroprotective strategies is hampered by our limited understanding of the mechanisms underlying these vascular changes. The aim of my research is to advance our understanding of the abnormal physiological processes associated with NAFLD, focusing on the brain and cerebrovascular system. I hypothesise that reduced metabolic supply is responsible for the cognitive impairment and decreased quality of life reported in patients with NAFLD. I will investigate whether NAFLD induced changes in the brain's blood vessels can be reversed by resolving NAFLD, or if the cerebrovascular damage is irreversible, thus making the brain more fragile during ageing. I will address these aims by applying advanced imaging and molecular techniques to an appropriate animal model of NAFLD. I will test my hypothesis by analysing human biomedical data from obese patients, with and without NAFLD, and obese patients who lost weight and reversed NAFLD. This approach has the added advantage of increasing our understanding of the impact of a fatty liver disease on brain complications usually attributed to obesity only. NAFLD is a serious, yet underappreciated, health risk factor and a major substantial societal and economic burden, which includes reduced health-related quality of life and increased healthcare costs estimated to reach £289 billion in the UK and Europe in the next 10 years. The knowledge obtained by this research, will have direct impact on global policies towards the prevention and treatment of NAFLD and may ultimately lead to the development of novel and effective neuroprotective strategies.