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

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.