Macrophage metabolism in chronic metabolic disease
Heart disease is a condition that affects more than one million Canadians, and costs the Canadian healthcare system almost 21 billion dollars annually. Atherosclerosis is the buildup of cholesterol and immune cells in the lining of the arteries (atherosclerotic plaque), and is a leading cause of heart attack and stroke. In addition to heart disease risk factors such as obesity and type 2 diabetes, the way that our body handles the build up of cholesterol in the arteries is also very important. Specialized immune cells called macrophages are able to take up and store excess cholesterol, protecting the artery wall in the process. These macrophages have specialized pathways to then transfer the cholesterol they scavenge to the circulating lipoprotein “HDL”, which then carries the cholesterol to the liver, where it can be safely removed (this is why HDL-cholesterol is called the “good” cholesterol). This is known as reverse cholesterol transport. However, when this process is overwhelmed, cholesterol builds in macrophages, turning them into foam cells and causing atherosclerosis to progress. The AMP-activated protein kinase (AMPK) is an important metabolic regulator that ensures there is enough cellular energy, and has been shown to play important roles in carbohydrate, protein and lipid metabolism. We have evidence to suggest that AMPK favourably alters lipid metabolism and are interested in determining the role of AMPK in macrophages and atherosclerosis. We use genetically engineered mice that are lacking the AMPK gene, as well as therapeutic compounds that specifically activate AMPK to test our hypotheses. The goal of our research is to investigate and uncover novel mechanisms that contribute to atherosclerosis and heart disease in the hopes of developing more effective prevention and therapeutic strategies.
CTL1 and the role of choline uptake in metabolic disease
Choline is an essential nutrient and a key molecular building block in mammals. A fundamental component of membrane phospholipids, choline is a precursor for the biosynthesis of the neurotransmitter acetylcholine, as well is an important donor of methyl groups for epigenetic regulation. Accordingly, choline deficiency can cause developmental impairments, decreased cognitive function, liver dysfunction, and abnormalities in lipid metabolism and gene regulation.
Choline is a positively charged molecule that requires transport to cross the lipid bilayer. Choline transporter-like protein-1 (CTL1) is a member of a new family of transporters and has been shown to be widely expressed and to transport choline at a high-affinity. The limited number of initial studies have used cell culture models to investigate the regulation and the associated choline transport of CTL1; however, there are no studies that have addressed the importance of CTL1 in a physiological animal model. Our research involves generating and characterizing a novel knockout mouse model, where the CTL1 gene (Slc44a1) will be targeted for disruption (CTL1 KO) and represents the necessary next step to fully understand the role of CTL1 in the transport and subsequent metabolism of choline in the body.