Gene

Biogenesis

Context (archaeology)

Cell biology

Membrane protein

Diacylglycerol kinase

Biology

Integral membrane protein

Endocrinology

Signal transduction

Biochemistry

Endoplasmic reticulum

Insulin

Organelle

Paleontology

Membrane

Protein kinase C

Lipid droplet

Insulin resistance

Lipotoxicity

Phosphatidylethanolamine

Phospholipid

Chemistry

Membrane contact site

Biophysics

Phosphatidylcholine

eLife

Cells store energy in the form of neutral lipids (NLs) packaged into micrometer-sized organelles named lipid droplets (LDs). These structures emerge from the endoplasmic reticulum (ER) at sites marked by the protein seipin, but the mechanisms regulating their biogenesis remain poorly understood. Using a combination of molecular simulations, yeast genetics, and fluorescence microscopy, we show that interactions between lipids’ acyl-chains modulate the propensity of NLs to be stored in LDs, in turn preventing or promoting their accumulation in the ER membrane. Our data suggest that diacylglycerol, which is enriched at sites of LD formation, promotes the packaging of NLs into LDs, together with ER-abundant lipids, such as phosphatidylethanolamine. On the opposite end, short and saturated acyl-chains antagonize fat storage in LDs and promote accumulation of NLs in the ER. Our results provide a new conceptual understanding of LD biogenesis in the context of ER homeostasis and function.

Pre-existing bilayer stresses modulate triglyceride accumulation in the ER versus lipid droplets