Regulation of Cytoplasmic Lipid Droplet Mobilization in Intestinal Enterocyte

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Most mammals use dietary fats as their major energy source. Handling of dietary fats in the gut plays crucial roles in whole-body energy homeostasis and physiology, with far-reaching impacts on other parts of the body and the overall system. My long-term vision for an NSERC-funded research program is to define the regulatory mechanisms that govern lipid handling in the gut and to determine how they are integrated with systemic biology. Dietary fats are digested and taken up by gut absorptive cells (enterocytes). In the enterocyte, the majority of absorbed fats are packaged into lipoprotein particles that are secreted from the cells to deliver energy to the body. A portion of the dietary fats form cytoplasmic lipid droplets (CLDs) in the enterocytes. CLDs are intracellular organelles that have diverse biological functions, abnormalities of which are linked to cellular stresses. CLDs are mobilized through lipolysis to release fatty acids that are directed to lipoprotein secretion or other essential cellular functions. Being able to control CLD mobilization and to partition fatty acids among various biological needs is essential for maintaining both local and systemic functions. However, to date, very little is known about the regulation of CLD mobilization and metabolic fates in gut enterocytes. My short-term goal during this 5-year NSERC-funded program is to systemically identify and characterize molecular mediators of lipid metabolism in gut enterocytes. I plan to build upon my strong expertise in gut lipid metabolism and my most recent findings, using innovative and integrative approaches, to 1) examine CLD dynamics, 2) identify proteins and phospholipids that mediate CLD mobilization, and 3) elucidate the functional roles of proteins that regulate CLD mobilization. Experiments will be carried out in an animal model I have successfully established. CLDs will be analyzed with imaging. Proteins and phospholipids in whole enterocytes, intracellular organelles (CLDs, endoplasmic reticulum), and secreted products will be analyzed with proteomics and lipidomics. The role of candidate and newly identified proteins will be examined in vivo with protein inhibitors. This program offers cutting-edge HQP training opportunities, as well as enriching intellectual environment for making discoveries that improve our understanding of a fundamental aspect of biological system. Findings from these studies will not only reveal how lipids are trafficked and partitioned among multiple cellular functions, but also open opportunities for mitigating cellular stresses. Considering the nutritional and environmental stresses faced by modern society, such advancements in knowledge may help develop novel coping strategies and improve the overall wellbeing of mammalian life.