Retinyl esters form lipid droplets independently of triacylglycerol and seipin.

Martijn R Molenaar ,Kamlesh K Yadav ,Roger Schneiter ,Muriel Mari ,Arie B Vaandrager ,Maya W Haaker ,Xavier Prieur ,Martin Houweling ,Lucie Caillon ,Alexandre Toulmay ,Vineet Choudhary ,Tsjerk A Wassenaar ,Abdou Rachid Thiam ,William A Prinz ,Fulvio Reggiori ,Aymeric Chorlay ,Ivan Lukmantara ,Richard Wubbolts ,Hongyuan Yang ,J Bernd Helms

doi:10.1083/jcb.202011071

Abstract

Lipid droplets store neutral lipids, primarily triacylglycerol and steryl esters. Seipin plays a role in lipid droplet biogenesis and is thought to determine the site of lipid droplet biogenesis and the size of newly formed lipid droplets. Here we show a seipin-independent pathway of lipid droplet biogenesis. In silico and in vitro experiments reveal that retinyl esters have the intrinsic propensity to sequester and nucleate in lipid bilayers. Production of retinyl esters in mammalian and yeast cells that do not normally produce retinyl esters causes the formation of lipid droplets, even in a yeast strain that produces only retinyl esters and no other neutral lipids. Seipin does not determine the size or biogenesis site of lipid droplets composed of only retinyl esters or steryl esters. These findings indicate that the role of seipin in lipid droplet biogenesis depends on the type of neutral lipid stored in forming droplets.

Highlights

Lipid droplets (LDs) form a ubiquitous class of organelles that store neutral lipids for a multitude of functions
Inhibition of DAG O-acyltransferase 1 (DGAT1) activity in CHO-k1 cells expressing lecithin: retinol acyltransferase (LRAT)-GFP showed no inhibition of retinyl esters (REs) synthesis, which confirms that LRAT is the primary RE-synthesizing enzyme (Fig. S1 D)
Our findings show the existence of a seipin-independent route for LD biogenesis driven by production of the neutral lipid RE by LRAT

Summary

Introduction

Lipid droplets (LDs) form a ubiquitous class of organelles that store neutral lipids for a multitude of functions. In the most prevalent view, LD formation is primarily driven by triacylglycerol (TAG) synthesis at the ER (Choudhary et al, 2015; Thiam and Foret, 2016; Walther et al, 2017). Seipin has been suggested to determine the site of LD biogenesis in the ER (Chung et al, 2019; Salo et al, 2019), to regulate the flow of neutral lipids and proteins from the ER to nascent LDs at ER–LD contacts (Grippa et al, 2015; Salo et al, 2019; Wang et al, 2014), and to regulate lipid metabolism at LD biogenesis sites (Renne et al, 2020). Seipin was shown to trap TAGs in the ER bilayer via luminal hydrophobic helices (Prasanna et al, 2021; Zoni et al, 2021)

Methods

Results

Conclusion