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

大量研究表明，不健康的生活方式和肥胖对大脑的有害影响，以及与患其他神经疾病(如痴呆症)的风险增加有关。非酒精性脂肪性肝病(NAFLD)是一种严重的肝脏疾病，常与其他慢性疾病并存，导致全球多病(定义为同一人同时发生多种慢性疾病)的健康危机。非酒精性脂肪性肝病影响全球约五分之一的人，肥胖者的患病率最高。现在越来越清楚的是，NAFLD正在影响包括大脑在内的其他器官，它与认知能力受损、抑郁情绪、焦虑、冷漠和大脑加速老化有关。大脑消耗了我们吸入的20%的氧气和20%的葡萄糖，氧气和代谢底物都通过血液输送到大脑。因此，血液供应不足会导致代谢缺陷，最终导致细胞损伤，导致认知能力下降和神经退化，就像阿尔茨海默病和衰老一样。为了维持适当和充足的能量供应，大脑有一个错综复杂的血管网络，通过提供氧气和营养物质，以及通过确保代谢废物的清除，有效地维持大脑代谢的动态平衡。我的研究表明，NAFLD与大脑中血管密度的下降有关，这会导致氧气供应减少。仅这一点就可能导致认知和行为的改变，以及报告的NAFLD患者患痴呆症的风险增加。然而，由于我们对这些血管变化机制的了解有限，神经保护策略的寻找受到了阻碍。我的研究目的是促进我们对与NAFLD相关的异常生理过程的理解，重点是脑血管系统。我假设代谢供应减少是NAFLD患者认知障碍和生活质量下降的原因。我将研究NAFLD引起的脑血管变化是否可以通过分解NAFLD来逆转，或者脑血管损伤是否不可逆转，从而使大脑在衰老过程中更加脆弱。我将通过将先进的成像和分子技术应用于合适的NAFLD动物模型来解决这些目标。我将通过分析肥胖患者的生物医学数据来验证我的假设，这些患者来自患有和不患有NAFLD的肥胖患者，以及减肥并逆转了NAFLD的肥胖患者。这种方法还有一个额外的好处，那就是增加了我们对脂肪肝对脑部并发症的影响的理解，这些并发症通常被归因于肥胖。非酒精性脂肪肝是一个严重但未得到重视的健康风险因素，也是一个重大的社会和经济负担，其中包括与健康相关的生活质量下降和医疗成本增加，预计未来10年英国和欧洲的医疗成本将达到2890亿GB。这项研究所获得的知识将直接影响全球预防和治疗NAFLD的政策，并最终可能导致开发新的有效的神经保护策略。

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.