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

Valeria Zoni,Rasha Khaddaj,Stefano Vanni,Pablo Campomanes,Abdou Rachid Thiam,Roger Schneiter

doi:10.7554/elife.62886

Abstract

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.

Highlights

Lipid droplets (LDs) are ubiquitous intracellular organelles that consist of a core of neutral lipids (NLs), mostly triglycerides (TG) and sterol esters, surrounded by a phospholipid (PL) monolayer (Walther and Farese, 2012)
The current model of lipid droplets (LDs) formation posits that after synthesis in the endoplasmic reticulum (ER) membrane, TG molecules accumulates at ER sites marked by seipin (Salo et al, 2019; Choudhary et al, 2020; Chung et al, 2019), that acts as a nucleation seed for the formation of a nascent TG lens that will subsequently grow into a mature LD
Alterations in lipid homeostasis result in defects in LD formation (Adeyo et al, 2011; Santinho et al, 2020; Cohen et al, 2015; Vevea et al, 2015; Wolinski et al, 2015) in some cases promoting non-negligible accumulation of TG in the ER (Adeyo et al, 2011; Cartwright et al, 2015) and alterations in ER morphology (Adeyo et al, 2011; Vevea et al, 2015; Wolinski et al, 2015). These experiments suggest that a detectable accumulation of TG in the ER is a hallmark of non-physiological conditions, under which proper LD formation does not take place; on the other hand, they indicate that seipin-independent ER properties, such as its lipid composition, can significantly alter the propensity of LD formation

Summary

Introduction

Lipid droplets (LDs) are ubiquitous intracellular organelles that consist of a core of neutral lipids (NLs), mostly triglycerides (TG) and sterol esters, surrounded by a phospholipid (PL) monolayer (Walther and Farese, 2012). Because of this unique composition, they are the cellular sites responsible for energy and lipid storage and they play a central role in lipid and cellular metabolism (Walther and Farese, 2012; Gao and Goodman, 2015; Pol et al, 2014; Olzmann and Carvalho, 2019). Deletion of other proteins with very different functions, such as the lipid phosphatase Pah (Adeyo et al, 2011) or the membrane-shaping protein Pex together with seipin (Wang et al, 2018), results in a more pronounced phenotype, with the majority

Methods

Results

Conclusion