FOR 5815:  Structural and functional lipid droplet heterogeneity

• Subject Area: Biology ; Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538651361

Lipid droplets (LDs) are key organelles of cellular lipid homeostasis. They exhibit a remarkable dynamic plasticity in molecular composition, number, localization, and appearance. This LD heterogeneity occurs at multiple levels, resulting in the formation of specific subpopulations that differ across intracellular space, between neighboring cells of the same or different types, and between healthy and diseased conditions. The surface of LDs consists of a phospholipid monolayer with associated enzymes as well as structural and regulatory proteins. The LD surface not only represents the critical interface between the neutral lipid core and the surrounding aqueous cellular environment, but is also a fundamental determinant of LD heterogeneity. This is clearly evident by the selective association of specific proteins to different LD subpopulations. Additional factors determining LD heterogeneity include the formation of contact sites with other organelles, the presence of different neutral lipid classes, LD-LD clustering or dispersion, differences in LD size and number, and the interaction of pathogenic agents with specific LD subpopulations. Intracellular LD heterogeneity enables not only the sub-compartmentalization and regulation of central LD functions, i.e., efficient lipid storage and lipolysis, but is also tied to the corresponding complex signaling networks that relate to energy homeostasis and substrate channeling. It is becoming increasingly evident that significant progress in LD biology demands a deeper understanding of LD heterogeneity. The overarching hypothesis of the FOR is that LD heterogeneity is an essential feature of eukaryotic cells. We postulate that dynamic LD heterogeneity and the cellular environment are closely intertwined, with each influencing and responding to the other. This bidirectional relationship allows cells to respond optimally to different conditions, especially to nutrient fluctuations and prevalent pathophysiological challenges. Thus, the central goal of the FOR is to elucidate the functional implications of LD heterogeneity in health and disease. Specifically, we will: I) Establish novel methods to purify and characterize LD subpopulations, II) Elucidate the contribution of LD heterogeneity to the regulation of lipid metabolism, III) Identify proteins and molecular machineries that are relevant to achieve and maintain LD heterogeneity, IV) Determine the functional links of organelle contact sites and subcellular organization to LD heterogeneity.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Herker, Eva )
• Deciphering lipid droplet heterogeneity using functionalized lipids (Applicants Brügger, Britta ;  Herker, Eva )
• Deciphering the function of lipid droplet subsets in flavivirus infection (Applicant Herker, Eva )
• Function of perilipin 3 in lipid droplet heterogeneity and metabolism (Applicant Füllekrug, Joachim )
• Interplay between hepatitis C virus and the hepatic lipid droplet mosaic (Applicant Vieyres, Ph.D., Gabrielle )
• Lipid droplet heterogeneity in cancer proliferation and stress resistance (Applicants Schulze, Almut ;  Snaebjoernsson, Marteinn )
• Proteomic and lipidomic profiling of retinol ester lipid droplets in hepatic stellate cells (Applicant Krahmer, Natalie )
• Structure-composition-function relation in LD physiology & disease (Applicant Mahamid, Ph.D., Julia )
• Systematic analysis of tethered lipid droplet subpopulations (Applicant Bohnert, Maria )

• Spokesperson: Professorin Dr. Eva Herker