Grant: Operating Grant

Regulation of intracellular cholesterol levels is crucial for cell function. ABCA1 is a critical protein for maintaining proper cholesterol levels in a variety of cell types by transporting excess cholesterol out of cells. Failure of ABCA1 to function properly leads to problems in many cell types. For example, if ABCA1 does not work properly in the liver and intestine, there is an inability to produce HDL or 'good' cholesterol which can result in an increased incidence of cardiovascular disease. If ABCA1 does not work normally in the pancreas, insulin is not properly secreted and can result in an increased risk for type-2-diabetes, the fastest growing disease in Canada. Failure of ABCA1 to work in the brain leads to inflammation and problems in communication between neurons which can lead to neurodegenerative disorders such as dementia, which Alzheimer's Disease International estimates afflicts more than 35 million people worldwide. Due to the importance of ABCA1 in the proper functioning of various tissues, it is vital that we understand how to regulate ABCA1 activity. Previous studies identified a way to effectively regulate ABCA1 at the level of the gene. Unfortunately, the benefits of increasing ABCA1 through these means are compromised by a variety of deleterious off-target effects. Our work aims to understand alternate pathways to regulate ABCA1 function in different tissues safely and effectively with minimal off-target effects. We will focus on two pathways, one involving the role of a lipid known as palmitate in controlling the location of ABCA1 in a cell, and another involving the role of microRNAs in controlling ABCA1 protein levels in a cell, both of which are correlated to ABCA1 activity levels. This work will provide insights into novel mechanisms of regulating ABCA1 and in doing so; identify means of controlling ABCA1 activity in different tissues, focusing on the liver, the pancreas, the brain and adipose tissue.