Classifying ABC Transporters in the Metabolically Active Tissues

包括肥胖症和2型糖尿病在内的代谢性疾病的负担日益加重，这是全球医疗保健系统的一个重大问题。2016年，19亿人被归类为超重或肥胖，全球每11人中就有1人患有最常见的糖尿病，即2型糖尿病。代谢性疾病与多种营养稳态功能障碍相关，包括胰岛素抵抗、血糖升高（糖尿病）、血脂异常和肝脂肪变性。这些相关问题导致疾病负担加重，仅糖尿病就消耗了整个NHS预算的约10%。因此，确定治疗靶点以纠正这种营养稳态功能障碍对于减轻肥胖和糖尿病的影响至关重要。ATP结合盒转运蛋白（ABC转运蛋白）是一个膜整合蛋白超家族，它利用ATP水解产生的能量将底物转运过膜。ABC超家族中有250多个成员可以被认为是“进口商”或“出口商”。虽然输入者仅存在于原核生物中，但真核生物和原核生物都具有ABC转运蛋白，其功能是将底物输出到胞质溶胶外，进入细胞器或输出到细胞外。人类有48种不同的ABC转运蛋白，其中几种转运脂质，包括转运磷脂和胆固醇的ABCA 1，转运极长链脂肪酸（VLCFA）的ABCD 1和转运胆固醇的ABCG 5/8，这表明了治疗血脂异常的潜在靶点。 拟议的项目将研究ABC转运蛋白在脂质代谢中的作用，使用代谢组织的细胞模型（胰腺β细胞，肌肉细胞和肝细胞），动物模型和肥胖和/或糖尿病或心血管疾病患者的血液样本。该项目将阐明ABC转运蛋白在这些脂质如何循环和代谢中的相对重要性，以及它们是否介导任何有害的细胞效应，如胰腺β细胞和肝脏脂肪变性中的脂毒性。

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.