Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism

项目总结：“脂滴分解代谢中脂质异质性的机制”

Project Summary: "Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism" Lipid droplet (LD) catabolism is a fundamental process that fuels energy-intensive cellular tasks like migration, differentiation, and survival through periods of low nutrient availability. Aberrant LD catabolism is recognized in several disease pathologies including fatty liver, obesity, diabetes, kidney disease and cancer. Because LD catabolism plays a foundational role in cell behavior, detailed mechanistic knowledge of this process has the potential to reveal novel targets for potential therapy. This project will determine mechanisms by which cells access the stored LD fuel. LDs play critical roles in cell metabolism by storing intracellular fat in nearly every cell type across multiple species. Surrounded by a unique phospholipid monolayer, LDs contain abundant neutral lipids in the form of triacylglycerol (TAG) and cholesterol ester (CE) that can be utilized for energy production via mitochondrial β-oxidation. Release of these stored lipids requires synergy between two catabolic processes: 1) lipolysis, in which β-adrenergic/cAMP stimulation recruits the cytoplasmic lipase adipose triglyceride lipase (ATGL) to the LD surface, and 2) lipophagy, a terminal stage of catabolism in which LDs are trafficked for lysosomal degradation via autophagic and/or endosomal vesicles. Preliminary data from our laboratory supports our central hypothesis that lipid species within the LD monolayer are modulated by lipolysis and lipophagy enzymes during LD catabolism. In Aim 1, we will determine the role of the lipolysis enzyme ATGL in producing DAG on the LD surface to recruit DAG effectors such as protein kinase C. In Aim 2, we will determine the regulation of phosphatidylinositol phosphorylation during LD trafficking to lysosomes. The results gained from the proposed research will provide a mechanistic understanding of lipid droplet trafficking and catabolism as a result of modulation of the LD monolayer. Moreover, this research will aid in future development of larger research project grant applications.