Lipid droplets are organelles that store lipids in cells. They were previously thought to be simple lipid storage depots, but are now recognized as complex organelles with multiple functions. Lipid droplets have a phospholipid monolayer surrounding a core of neutral lipids. They form through budding from the endoplasmic reticulum and interact dynamically with other organelles. Proteins associated with lipid droplets regulate lipid metabolism and storage. Lipid droplets are also involved in non-canonical functions like sequestering proteins and histones. Dysfunctions in lipid droplet proteins can lead to diseases.

1. Not Just Fat: The Structure and
Function of the Lipid Droplet
Toyoshi Fujimoto & Robert G. Parton
Presented by Bang Tran, Dharma Varapula,
and Edward Waddell

2. Introduction
• Known as mere deposits of lipid esters for many years
• Redefined as authentic organelles with multiple functions
• Lipid metabolism
• Lipid storage function in white adipocytes
• Various new functions
• Diseases related to LDs

3. Structure and Biogenesis of the
Lipid Droplet (LD)

4. LD’s Structure
• Diameter
• 0.1 to 5 µm in non-adipocyte
• 100 µm in white adipocyte
• Outside
• Phospholipid monolayer
• Inside
• Lipid Esters
• Amphiphilic proteins

5. Structure
• Phospholipid monolayer
• Phosphatidylchloline (PC)
• Phosphatidylethanolamine
(PE)
• Phosphatidylinositol
• lysoPC and lysoPE
• LD Core
• Triglycerides
• Cholesterol ester
• Amphiphilic protein Guo, et al. (2009)

6. Biogenesis
• 3 proposed models
1. Budding from the ER
covered by the cytoplasmic
leaflet
2. “Hatching” from a bicellular
structure
3. Budding from a vesicle
• Not spontaneous form but
require some active
mechanism
Guo, et al. (2009)

7. Functions of LDs

8. Functions of LDs
Can be classified into:
Most of these functions can be ascribed to:
• Surface proteins, commonly PAT proteins
• Availability of organic/hydrophobic phase within the cell
Canonical (or lipid-related) Non-canonical
1 Storage of lipid esters Capturing faulty proteins, histones
2 Lipid metabolism regulation Signaling

9. PAT Proteins
Regulate the lipid storage and metabolism
● PLIN 1 (perilipin) - in adipocytes and steroidogenic cells
● PLIN 2 (ADRP), PLIN 3 (TIP47) - almost everywhere
● PLIN 4 (S3-12) - largely adipocytes
● PLIN 5 (OXPAT/MLDP/LSDP5) - fatty acid oxidation sites
(liver, muscle, brown adipocytes)

10. Lipolysis of lipid esters
CA catecholamines (dopamine,
isoproterenol, etc)
βAR β-adrenergic receptor (GPCR)
cAMP cyclic-AMP (secondary
messenger)
PKA Protein kinase A
HSL Hormone-sensitive lipase
ATGL Adipose triglyceride lipase
CGI-58 a co-activator of ATGL
Bickel, et al. (2009)

11. Lipid Metabolism Regulation
Mutant lacking neutral lipids
displayed delayed growth and
morphological defects.
Loss of ATGL (lipase) ortholog
induced lethality in embryos of
Drosophila melanogaster - Gronke,
et al. (2005).
- de novo fatty acid synthesis
pathways were undisturbed
- this implies lipids from LDs are in
some way preferred
Petschnigg, et al. (2009)

12. Non-canonical functions
Hydrophobic proteins (ApoB, α-synuclein) temporarily stored in
LDs for degradation
- how large lipidated-ApoB moves from ER to LD through the
degrading cytosol is not clear
Free histones (toxic and not hydrophobic) are sequestered in
LD of Drosophila embryo for release at a later stage
- why cell chooses LD (fluctuating surface area and
numbers) over conventional membranes not clear

13. LDs in a Cellular Context

14. LD interactions with Other
Organelles
• LD-ER interaction may be a
mechanism which allows stored
lipids in LDs to become mobilized
for use in other cellular sites.
• LDs perform a “kiss-and-run”
contact with phagosomes in order
to supply them with arachidonic
acid for NADPH oxidase
activation.
• LDs form a close relationship with
mitochondria and peroxisomes.
This is to allow fatty acids
liberated by lipolysis to enter into
β-oxidation. Sturmey, R. G., et al. (2006)

15. LD interaction with Caveolae and Caveolins
• Caveolins are a family of integral membrane proteins that associate with
LDs in fatty-acid loaded cells and regenerating hepatocytes.
• Caveolins form the framework of caveolae, which are specialized types
of lipid rafts rich in cholesterol, sphingolipids, and proteins. Caveolae are
important for several functions in signal transduction.
• Caveolin-1 is translocated to LDs through a hemi-fusion interaction
between the vesicular membrane and LD. Caveolin-1 is associated with
LD function and lipid storage in adipocytes.
Fernandez, et al. (2006)

16. LD Motility
• Motility of LDs is essential to regulate
their distribution within the cell and
how they interact with other
organelles.
• LDs show both microtubule-based
directional long-distance and random
short-distance types of movement.
• Dynein and kinesin-1 were found
to be associated with LDs
• LSD2, a PAT protein homolog in
Drosophila, regulates LD movement
by coordinating dynein and kinesin-1.
• Manipulation of LSD2 shows that
LSD2 is required for normal lipid
storage by allowing for the
formation of larger LDs through
microtubule based movements.
Welte, et al. (2005)

17. LD Motility
Welte, et al. (2005)

18. LDs and Disease

19. LDs and Motor Neuron Disease
• Spartin/SPG20, a LD protein, binds to TIP47 and competes
with ADRP for LD association.
• An E3 ligase, WWP1, regulates the amount of
Spartin/SPG20 thus regulating lypolysis by adjusting the
TIP47:ADRP ratio.
• Spartin/SPG20 mutants that cannot compete with ADRP
cause Troyer syndrome, a motor neuron disease.
• This defect appears to be caused by aberrant turnover of
LD lipids.

20. References
• Fujimoto, T., Parton, R. G. (2011) Not Just Fat: The Structure and Function of the Lipid Droplet. Cold Spring
Harb Perpect Biol. 3:a004838.
• Guo, Y., Cordes, K., Farese, R., and Walther, T. (2009). Lipid Droplets at a glance. Journal of Cell Science.
122:749-752.
• Bickel, P. E., Tansey, J. T., Welte, M. A. (2009) PAT proteins, an ancient family of lipid droplet proteins that
regulate cellular lipid stores. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1791
(6): 419-440.
• Petschnigg, J., Wolinski, H., Kolb, D., Zellnig, G., Kurat, C. F., Natter, K., Kohlwein, S. D. (2009) Lipids and
Lipoproteins: Metabolism, Regulation and Signaling. J. Biol. Chem. 284: 30981-30993.
• Gronke, S., Mildner, A., Fellert, S., Tennagels, N., Petry, S., Muller, G., Jackle, H., Kuhnlein, R. P. (2005)
Brummer lipase is an evolutionarily conserved fat storage regulator in Drosophila. Cell Metab. 1:323:330.
• Fernandez, M., Albor, C., Ingelmo-Torres, M., Nixon, S., Ferguson, C., Kurzchalia, T., Tebar, F., Enrich, C.,
Parton, R., and Pol, A. (2006) Caveolin-1 is essential for liver regeneration. Science. 313: 1628–1632.
• Sturmey, R., O’Toole, P., and Leese, H. (2006) Fluorescence resonance energy transfer analysis of
mitochondrial:Lipid association in the porcine oocyte. Reproduction. 132: 829–837.
• Welte, M., Cermelli, S., Griner, J., Viera, A., Guo, Y., Kim, D., Gindhart, J., and Gross, S. (2005) Regulation of
lipid-droplet transport by the perilipin homolog lsd2. Curr Biol. 15: 1266–1275.