Lipid Droplet Biogenesis, Metabolism, and Regulation in short (guide for students)

1. Introduction

Lipid droplets (LDs) are specialized cytosolic organelles that primarily store neutral lipids, notably triacylglycerols (TAG) and sterol esters (SE). Once thought to be inert fat depots, LDs are now recognized as highly dynamic hubs at the intersection of lipid metabolism, energy regulation, and cell signaling.

2. Lipid Droplet Biogenesis

2.1 ER Nucleation and Lens Formation

LD biogenesis begins in the endoplasmic reticulum (ER), where enzymes like DGAT1/2 catalyze the synthesis of TAG, which accumulates between the bilayer leaflets, forming a neutral lipid "lens."

2.2 Budding and Scission

Proteins such as seipin (BSCL2) are critical for the proper nucleation and morphology of LDs. Mutations in seipin cause congenital generalized lipodystrophy, highlighting its essential role.

2.3 Expansion and Coalescence

After budding into the cytosol with a phospholipid monolayer, LDs expand by:

Local TAG synthesis, facilitated by enzymes like GPAT and AGPAT at LD-ER contact sites.
Fusion events, mediated by proteins like CIDEA and CIDEC (FSP27), promoting larger LDs.

3. Lipid Droplet Metabolism

3.1 Lipid Storage and Buffering

LDs sequester excess fatty acids and cholesterol, preventing lipotoxic stress, ER stress, and mitochondrial dysfunction.

3.2 Lipolysis: PKA and Perilipins

Perilipins (PLINs) are structural proteins coating LDs, acting as gatekeepers for lipases.
Upon catecholamine stimulation, PKA phosphorylates PLIN1, causing conformational changes that allow ATGL (adipose triglyceride lipase) and HSL (hormone-sensitive lipase) to access and hydrolyze TAGs.

3.3 Lipophagy

LDs can also be degraded via selective autophagy (lipophagy), where LDs are delivered to lysosomes for breakdown.

4. Regulation of Lipid Droplet Dynamics

4.1 Nutrient and Energy Sensors: TORC1 and AMPK

mTORC1 senses nutrient abundance, stimulating lipogenesis and LD accumulation.
AMPK, activated under energy deficit (high AMP/ATP), inhibits ACC, reducing malonyl-CoA and favoring fatty acid oxidation over storage. AMPK also indirectly limits LD expansion.

4.2 Hormonal Control

Insulin promotes lipid synthesis and LD growth by activating SREBP1c and lipogenic enzymes.
Catecholamines (epinephrine, norepinephrine) elevate cAMP, activating PKA, leading to PLIN1 phosphorylation and enhanced lipolysis.

4.3 Transcriptional Control

PPARγ drives expression of genes involved in lipid uptake and storage.
SREBP1c regulates fatty acid synthesis enzymes, contributing to LD formation.

5. Genetic Diseases Linked to Lipid Droplet Metabolism

Seipin mutations (BSCL2) cause lipodystrophy, underscoring defective LD nucleation.
PLIN1 mutations lead to partial lipodystrophy with metabolic complications like insulin resistance and hypertriglyceridemia.
ATGL (PNPLA2) deficiency causes neutral lipid storage disease with myopathy (NLSDM), characterized by excessive TAG accumulation in muscle.

Your studies (PMID:33010453, PMID:34793861) also highlight how mutations affecting LD-associated proteins disrupt energy homeostasis and are linked to severe metabolic derangements. These works further reveal the intricate balance between lipid storage and utilization, emphasizing the clinical relevance of LD biology.

6. Lipid Droplets in Disease Contexts

6.1 Metabolic Syndrome and NAFLD

Excessive LD accumulation in hepatocytes is a hallmark of non-alcoholic fatty liver disease (NAFLD). Dysregulation of LD turnover contributes to progression from simple steatosis to steatohepatitis.

6.2 Obesity and Insulin Resistance

In adipose tissue, altered LD dynamics impair lipid buffering, leading to ectopic lipid deposition in muscle and liver, driving insulin resistance.

6.3 Cardiomyopathies

Myocardial lipid accumulation, often from mutations in ATGL or PLINs, leads to cardiac lipotoxicity and heart failure.

7. Conclusion

Lipid droplets are central organelles orchestrating lipid storage and mobilization. Their biogenesis, metabolism, and regulation are tightly controlled by nutrient sensors (mTORC1, AMPK), hormonal pathways (PKA, insulin), and structural proteins (perilipins, seipin). Dysregulation of these pathways underlies a range of metabolic diseases, from lipodystrophies to type 2 diabetes and cardiovascular disease.

References

Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20(3):137-155. doi:10.1038/s41580-018-0085-z. PMID: 30626978.
Walther TC, Chung J, Farese RV Jr. Lipid Droplet Biogenesis. Annu Rev Cell Dev Biol. 2017;33:491-510. doi:10.1146/annurev-cellbio-100616-060608. PMID: 28992438.