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

非酒精性脂肪性肝病(NAFLD)涵盖了一系列由脂质堆积引起的肝脏疾病，使其成为全球最常见的肝病之一，影响到24%的人口。由于饮食中脂肪摄入量的增加，这种情况在西方人群中的患病率更高，在英国，三分之一的人被认为在肝脏中积累了早期脂肪。非酒精性脂肪肝的范围从脂肪变性，即肝脏中的脂肪堆积，到纤维化和肝硬变，即肝脏疾病的终末期。脂肪变性的定义是脂肪在肝细胞中积聚了5%，这不是由于过量饮酒造成的。它还与肥胖和2型糖尿病等代谢综合征密切相关。由于非酒精性脂肪肝是西方人群中肝脏疾病的主要原因，对该疾病的发展和进展的研究具有重要意义。众所周知，药物还会干扰脂肪酸氧化和线粒体功能，从而导致肝脏脂肪变性，导致特殊的肝脏毒性。然而，有证据表明，可能存在个体遗传差异，这可能会使人们更容易受到肝脏毒性的影响。脂肪肝的早期阶段(脂肪变性)到纤维化和肝硬变的进展有复杂的分子起源。个体因素在NAFLD发生的易感性和严重程度中起作用。能量代谢，包括线粒体呼吸，是脂肪酸氧化部位脂肪积累的关键因素之一。个体线粒体的功能是由核和线粒体遗传学的组合决定的，并可能进一步受到生活方式和疾病等环境因素的影响。线粒体DNA(MtDNA)是整个生物能量表型的关键因素。线粒体DNA是母系遗传的，单核苷酸多态(SNPs)导致线粒体单倍群，形成线粒体基因型的基础。每个单倍群在线粒体活性和能量代谢方面存在功能差异。先前的研究表明，不同的线粒体单倍群可以影响肝脏的能量代谢，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在基础和异常脂肪酸代谢方面对细胞代谢的独特影响，特别是脂肪变性和肝毒性的发生。这将使用一种先进的肝脏特异性传递线粒体杂交体的体外模型来进行。这些杂交体将被用来定义线粒体单倍群对能量代谢途径和脂肪变性的发展的影响，以及潜在的分子机制。进一步的研究将检验暴露于线粒体毒素后的脂肪酸氧化失调和脂肪堆积的影响。

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.