Defining the importance of mitochondrial genotype in determining individual variation in hepatic fatty acid oxidation and dysregulation

确定线粒体基因型在确定肝脂肪酸氧化和失调个体差异中的重要性

• 批准号: 2277368
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2277368
• 关键词: Defining; importance; mitochondrial; genotype; determining

Non-alcoholic fatty liver disease (NAFLD) covers a range of liver conditions caused by lipid accumulation, which makes it one of the most prevalent liver diseases worldwide, affecting 24% of the population. The prevalence is higher in the western population due to increased fat intake in the diet, with 1 in 3 people in the UK believed to have early stages of fat accumulation in the liver. NAFLD ranges from steatosis, the accumulation of lipid in the liver, to fibrosis and cirrhosis, the end stages of liver disease. Steatosis is defined by a 5% accumulation of lipids in the hepatocyte which is not due to excessive alcohol consumption. It is also strongly linked with metabolic syndromes such as obesity and type-2 diabetes. As NAFLD is the leading cause of liver disease in the western population, research into the development and progression of the disease is of high importance. Drugs have also been known to interfere with fatty acid oxidation and mitochondrial function which can then lead to steatosis in the liver, causing idiosyncratic hepatotoxicity. However, there is evidence to suggest that there could be individual genetic differences which can make people more susceptible to hepatotoxicity. The early stages of fatty liver (steatosis) to the progression of fibrosis and cirrhosis has complex molecular origins. Individual factors play a role in the predisposition to develop NAFLD and its severity. Energy metabolism, including mitochondrial respiration, is one of the key elements in lipid accumulation at the site of fatty acid oxidation. Individual mitochondrial function is determined through a combination of nuclear and mitochondrial genetics and can be further influenced by environmental factors such as lifestyle and disease. The mitochondrial DNA (mtDNA) is the key contributor to the overall bioenergetic phenotype. MtDNA is maternally inherited, with single nucleotide polymorphisms (SNPs) giving rise to mitochondrial haplogroups, which form the basis of the mitochondrial genotype. Each haplogroup has functional differences in mitochondrial activity and energy metabolism. Previous research has shown that different mitochondrial haplogroups can have an effect on hepatic energy metabolism, in particular the dysregulation of fatty acid oxidation. The aim of the project is to investigate the singular effect of mitochondrial genotype upon cellular metabolism with respect to basal and aberrant fatty acid metabolism, in particular the onset of steatosis and hepatotoxicity. This will be carried out using an advanced in vitro model of liver-specific transmitochondrial cybrids. These cybrids will be used to define the effect of mitochondrial haplogroup on energy metabolism pathways and the development of steatosis, as well as the underlying molecular mechanisms. Further investigation will examine the effect of fatty acid oxidation dysregulation and lipid accumulation after exposure to mitochondrial toxins.

非酒精性脂肪性肝病（NAFLD）涵盖了由脂质积聚引起的一系列肝脏疾病，这使其成为全球最流行的肝脏疾病之一，影响24%的人口。由于饮食中脂肪摄入量增加，西方人群的患病率较高，英国有三分之一的人被认为在肝脏中有早期脂肪积累。NAFLD的范围从脂肪变性（肝脏中脂质的积累）到纤维化和肝硬化（肝脏疾病的终末期）。脂肪变性定义为肝细胞中5%的脂质积聚，这不是由于过量饮酒造成的。它也与代谢综合征如肥胖和2型糖尿病密切相关。由于NAFLD是西方人群中肝脏疾病的主要原因，因此研究该疾病的发展和进展非常重要。已知药物也会干扰脂肪酸氧化和线粒体功能，从而导致肝脏脂肪变性，引起特异质肝毒性。然而，有证据表明，可能存在个体遗传差异，这可能使人们更容易受到肝毒性的影响。脂肪肝（脂肪变性）的早期阶段到纤维化和肝硬化的进展具有复杂的分子起源。个体因素在发展NAFLD的倾向及其严重程度中起作用。能量代谢，包括线粒体呼吸，是脂肪酸氧化位点处脂质积累的关键要素之一。个体线粒体功能是通过细胞核和线粒体遗传学的结合来确定的，并且可以进一步受到环境因素如生活方式和疾病的影响。线粒体DNA（mtDNA）是整体生物能量表型的关键贡献者。线粒体DNA是母系遗传的，单核苷酸多态性（SNP）产生线粒体单倍型群，其形成线粒体基因型的基础。每个单倍型群在线粒体活性和能量代谢方面具有功能差异。先前的研究表明，不同的线粒体单倍型群可以对肝脏能量代谢产生影响，特别是脂肪酸氧化的失调。该项目的目的是研究线粒体基因型对细胞代谢基础和异常脂肪酸代谢的独特影响，特别是脂肪变性和肝毒性的发生。这将使用肝脏特异性transmitochondrial cybrids的先进体外模型进行。这些胞质杂种将用于确定线粒体单倍型群对能量代谢途径和脂肪变性发展的影响，以及潜在的分子机制。进一步的研究将检查暴露于线粒体毒素后脂肪酸氧化失调和脂质积累的影响。