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

了解 NAFLD 对大脑产生有害影响的机制

• 批准号: MR/X033287/1
• 负责人: Anna Hadjihambi
• 金额: $ 159.61万
• 依托单位: Foundation for Liver Research
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX033287%2F1
• 关键词: Understanding; mechanisms; underlying; detrimental; effects

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.

大量研究表明，不健康的生活方式和肥胖会对大脑产生不良影响，并与其他神经系统疾病（例如痴呆症）的风险增加相关。 NAFLD 通常与其他慢性病共存，导致全球多重发病率健康危机（定义为同一个人同时发生多种慢性疾病），全球约有五分之一的人受到 NAFLD 的影响，其中肥胖人群的患病率最高。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、情绪抑郁、焦虑、冷漠和大脑加速老化有关。大脑消耗我们吸入的 20% 的氧气和 20% 的葡萄糖。我们消耗氧气和代谢底物，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行性变，如阿尔茨海默病和衰老。维持在适当和充足的能量供应下，大脑有一个复杂的血管网络，可以通过输送氧气和营养物质以及确保代谢废物的清除来有效维持大脑代谢稳态。我的研究表明，NAFLD 与减少代谢废物有关。大脑中血管的密度，导致氧气供应减少，这可能是 NAFLD 患者认知和行为改变以及痴呆风险增加的原因。受到我们有限的阻碍我的研究目的是增进我们对与 NAFLD 相关的异常生理过程的理解，重点关注大脑和脑血管系统。我假设代谢供应减少是导致认知障碍和认知功能减退的原因。我将研究 NAFLD 引起的大脑血管变化是否可以通过解决 NAFLD 来逆转，或者脑血管损伤是否是不可逆转的，从而使大脑在治疗过程中变得更加脆弱。我将通过将先进的成像和分子技术应用于适当的 NAFLD 动物模型来实现这些目标。我将通过分析患有或不患有 NAFLD 的肥胖患者以及体重减轻并逆转 NAFLD 的肥胖患者的人类生物医学数据来检验我的假设。这种方法的另一个优点是增加我们对脂肪肝疾病对通常仅归因于肥胖的脑部并发症的影响的了解，NAFLD 是一种严重但未被充分认识的健康风险因素，也是一项重大的社会和经济负担。其中包括未来 10 年内英国和欧洲与健康相关的生活质量下降和医疗保健费用增加预计将达到 2890 亿英镑。这项研究获得的知识将对全球预防和治疗艾滋病的政策产生直接影响。 NAFLD 可能最终导致新型有效的神经保护策略的开发。