Importance of intestinal phosphatidylcholine supply in regulating lipid and trimethylamine metabolism

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Phosphatidylcholine (PC) is vital for the structural integrity of mammalian membranes and is the primary phospholipid in bile, lung surfactant, and plasma lipoproteins. In all nucleated mammalian cells, PC is synthesized from choline via the CDP-choline pathway, and the flux through this pathway is regulated by the activity of CTP:phosphocholine cytidylyltransferase (CT). An active PC biosynthesis is required for lipoprotein secretion from hepatocytes. During the past 5 years my NSERC-funded research has focused on understanding the role of dietary choline in regulating intestinal lipid metabolism. The long-term goal of this research program renewal is built on the momentum of my progress to elucidate the physiological consequences of impaired intestinal PC supply on dietary lipid absorption, circulating lipoprotein metabolism, and trimethylamine production (a minor choline metabolite produced by the microbiome). The overall working hypothesis is that de novo synthesis of intestinal PC is vital for normal lipid absorption, chylomicron production and secretion. Furthermore, we predict that circulating lipoproteins are a significant source of PC when intestinal supply is limiting. Finally, we hypothesize that de novo PC synthesis modulates the production of trimethylamine by the gut microbiome. The following specific aims will be addressed: ***1. Investigate the mechanisms by which intestinal PC availability regulates dietary TG absorption.***2. To determine the importance of intestinal PC metabolism on circulating lipoprotein homeostasis.***3. To understand how dietary and de novo PC supply modulates trimethylamine and trimethylamine-oxide production. ***The proposed program will contribute to our fundamental knowledge of intestinal PC metabolism across the lifespan. HQPs will use a multidisciplinary approach (including molecular, biochemical, and physiological techniques), dietary manipulation and novel animal models to delineate the biological consequences of impaired intestinal PC supply on circulating lipoprotein homoeostasis and microbiota trimethylamine production. The basic understanding of physiology and biochemistry of intestinal PC metabolism that will be gained from my NSERC research program will provide the mechanistic knowledge for future studies into the role intestinal PC homeostasis plays in the development or protection of chronic diseases, such as atherosclerosis and intestinal bowel disease.