Cells store the majority of their metabolic energy in cytosolic lipid droplets. These endoplasmic reticulum (ER)-derived organelles consist of a core of neutral lipids (mainly triglycerides and sterol-esters), which is uniquely encapsulated by a phospholipid monolayer. Proteins embedded into this membrane include key enzymes for the hydrolysis and synthesis of neutral lipids.
Lipid droplets are highly dynamic organelles that balance influx, storage and consumption of neutral lipids in nearly all cells of our body and are therefore central hubs in lipid metabolism. They are implicated in a range of human pathologies including hallmark diseases of our modern society such as obesity, diabetes, hepatic steatosis and cardiovascular disorders. However, next to nothing is known about the molecular mechanisms underlying protein targeting to lipid droplets, the biogenesis of lipid droplets from the ER membrane and the integration of lipid droplet function into lipid metabolism.
Figure 1: Lipid Droplet Biogenesis and Protein Targeting
Local accumulation of triglycerides (TG) triggers the formation of a lipid droplet (LD) from the cytoplasmic leaflet of the endoplasmic reticulum (ER) membrane, resulting in a phospholipid monolayer-encapsulated LD. Integral membrane proteins on LDs are uniquely embedded into the phospholipid monolayer via hydrophobic hairpin regions and expose all soluble domains towards the cytosol. Some of these hairpin proteins are initially inserted into the ER membrane and partition from the ER to LDs by unknown mechanisms (class I LD proteins). Class II LD proteins associate with the LD surface via amphipathic helices, lipid-anchors or protein-protein interactions and target LDs from the cytosol. The molecular details underlying LD biogenesis as well as mechanisms that govern the correct targeting and membrane insertion of LD-destined proteins remain enigmatic. (Figure taken from Dhiman et al., Seminars in Cell and Developmental Biology, 2020, doi: 10.1016/j.semcdb.2020.03.004)
Our lab investigates fundamental aspects of lipid droplet biogenesis and function. We recently discovered that lipid droplets share targeting machinery with peroxisomes for some of their membrane protein constituents (Schrul and Kopito, Nature Cell Biology 2016, doi: 10.1038/ncb3373). This suggests that the biogenesis and function of these two organelles with complementary roles in lipid metabolism is coordinated. Projects in our lab currently address three major questions:
- 1. What are the molecular mechanisms underlying protein targeting and insertion into the limiting membrane of lipid droplets?
- 2. How is lipid droplet biogenesis from the ER membrane regulated?
- 3. How do lipid droplets communicate with other lipid metabolizing organelles to adapt to metabolic changes?
We employ a range of biochemical and cell biological techniques including in vitro reconstitution experiments, protein-interaction studies, organelle / protein isolations, CRISPR/Cas9 genome editing, RNA interference, quantitative proteomics, lipidomics analyses as well as advanced fluorescence and electron microscopy.
Our long-term goal is to understand how aberrant lipid droplet function contributes to human pathologies such as obesity, diabetes or cardiovascular diseases, which will enable the identification of novel therapeutic targets.
Figure 2: Inter-Organelle Communication in Lipid Metabolism
Lipid droplets are central hubs in lipid metabolism as they dynamically store triglycerides (TG) under anabolic conditions and mediate hydrolysis of TG into diglycerides (DG) and fatty acids (FA) under catabolic conditions. While very long chain fatty acids (VLCFA) are beta-oxidized in peroxisomes, shorter fatty acids are imported into mitochondria via carnitines for beta-oxidation and ATP production. Peroxisomes produce ether lipids, which can be esterified and stored in LDs. LDs share targeting machinery (PEX19/PEX3) with peroxisomes for some of their membrane protein constituents, which may play a role in coordinating inter-organelle communication and adaptation of cells to metabolic changes.
Cooperative processes governing protein partitioning between membranes of distinct physicochemical properties (SFB1027 Project C9)
Lipid Droplets (LDs) create a unique physicochemical environment in the cell as their hydrophobic neutral lipid core is segregated from the aqueous cytosol by a phospholipid monolayer. The dynamic metabolic function of LDs relies on specific proteins that integrate into this membrane in a monotopic hairpin-type topology. This topology presumably facilitates partitioning of hairpin proteins from the endoplasmic reticulum bilayer membrane to LD monolayers; yet, the biophysical principles enabling hairpin proteins to reside in these distinct physicochemical membrane environments as well as the partitioning between them remain unknown. Within the scope of the SFB1027 we aim to determine which intrinsic protein features and which lipid-mediated parameters define a hairpin topology that allows bilayer-to-monolayer membrane partitioning. To this end a combination of biochemical and biophysical in vitro reconstitution experiments with molecular dynamics simulations is employed in a highly interdisciplinary approach.
Join us!
We are always interested in motivated graduate students and postdocs. If you are interested in joining our young and growing team, please contact me (Diese E-Mail-Adresse ist vor Spambots geschützt! Zur Anzeige muss JavaScript eingeschaltet sein!) with your CV, a statement of research interests and contact information for references. Prospective postdocs should apply early so that financial support through third party funding can be explored.
We also have a number of short-term/thesis projects available for motivated undergraduate students and are looking forward to hearing from you to discuss potential projects.
