Classifying ABC Transporters in the Metabolically Active Tissues

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The rising burden of metabolic disease, including obesity and type 2 diabetes mellitus is a substantial concern for healthcare systems worldwide. In 2016 1.9 billion people were classed as overweight or obese and worldwide 1 in 11 people have the most common form of diabetes, type 2. Metabolic disease is associated with a wide array of nutrient homeostasis dysfunction, including insulin resistance, elevated blood glucose (in diabetes), dyslipidaemia and hepatic steatosis. These associated issues drive disease burden which has led to diabetes alone consuming around 10% of the entire NHS budget. Identifying therapeutic targets to correct this nutrient homeostasis dysfunction is therefore paramount to mitigate the impacts of both obesity and diabetes. The ATP-binding cassette transporters (ABC transporters) are a superfamily of integral membrane proteins, which use energy from ATP hydrolysis to transport substrates across the membrane. There are more than 250 members in the ABC superfamily that can be thought of as 'importers' or 'exporters'. Whilst importers only exist in prokaryotes, both eukaryotes and prokaryotes possess ABC transporters that function to export substrates out of the cytosol, either into an organelle, or out of the cell. Humans have 48 different ABC transporters, and several of these transport lipids, including ABCA1 which transports phospholipids and cholesterol, ABCD1 which transports very long chain fatty acids (VLCFA) and ABCG5/8 which transports cholesterol, suggesting a potential target for treating dyslipidaemia. The proposed project will investigate the role of ABC transporters in lipid metabolism, using cell models of metabolic tissues (pancreatic beta-cells, muscle cells and hepatocytes), animal models and blood samples from patients with obesity and/or diabetes or cardiovascular disease. The project will elucidate the relative importance of ABC transporters in how these lipids circulate and are metabolised and whether they mediate any of the noxious cellular effects such as lipotoxicity in pancreatic beta-cells and hepatic steatosis.