Retinyl esters form lipid droplets independently of triacylglycerol and seipin

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

doi:10.1083/jcb.202011071

Cited by 25 publications

(21 citation statements)

References 64 publications

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“…Another possibility is that seipin acts in a step before lipid droplet homeostasis and this step is shared with both lipid droplet homeostasis and embryogenesis/lipid barrier synthesis (Figure 6F). Consistent with this hypothesis, biogenesis of lipid droplets that contain only retinyl or steryl esters does not depend on seipin (Molenaar et al, 2021), which suggests that seipin does not directly determine droplet formation. The shared function could be in ER phospholipid homeostasis (Fei et al, 2011a; Gao et al, 2019).…”

Section: Discussionmentioning

confidence: 71%

Contrasting effects of reduced phosphatidylcholine synthesis in absence of seipin: embryonic lethality goes down while lipid droplets get even larger

Zhu

Lam

Yang

et al. 2022

Preprint

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Seipin plays a vital role in lipid droplet homeostasis and its deficiency causes congenital generalized lipodystrophy type II in humans. It is not known whether the physiological defects are all caused by cellular lipid droplet defects. Loss-of-function mutation of seip-1, the C. elegans seipin ortholog, causes embryonic lethality and lipid droplet abnormality. We uncover nhr-114 and spin-4 as two suppressors of seip-1 embryonic lethality. Mechanistically, nhr-114 and spin-4 act in the “B12-one-carbon cycle-phosphatidylcholine (PC)” axis and reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants. Conversely, PC deficiency enhances the lipid droplet abnormality of seip-1 mutants. The suppression of seip-1 embryonic lethality by PC reduction requires polyunsaturated fatty acid (PUFA). Therefore, seipin and phosphatidylcholine exhibit opposite actions in embryogenesis, while they function similarly in lipid droplet homeostasis. Our results demonstrate that seipin-mediated embryogenesis is independent of lipid droplet homeostasis.Highlightsseip-1 suppressors act in the “B12-one-carbon cycle-PC” pathway.Reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants.Suppression of the embryonic lethality by PC reduction requires PUFA.Reduced PC synthesis enhances the large lipid droplet of seip-1 mutants.

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Section: Discussionmentioning

confidence: 71%

Contrasting effects of reduced phosphatidylcholine synthesis in absence of seipin: embryonic lethality goes down while lipid droplets get even larger

Zhu

Lam

Yang

et al. 2022

Preprint

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“…Recently, the expression of human lechitin retinol acyltransferase (LRAT) in no NLs cells was shown to lead to the formation of retinyl ester (RE)-containing LDs ( Molenaar et al, 2021 ). We tested whether the packaging of RE, an NL naturally not present in yeast, also required Sei1 and Ldb16.…”

Section: Resultsmentioning

confidence: 99%

Seipin concentrates distinct neutral lipids via interactions with their acyl chain carboxyl esters

Renne

Corey

Ferreira

et al. 2022

Journal of Cell Biology

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Lipid droplets (LDs) are essential for cellular lipid homeostasis by storing diverse neutral lipids (NLs), such as triacylglycerol (TAG), steryl esters (SE), and retinyl esters (RE). A proper assembly of TAG-containing LDs at the ER requires Seipin, a conserved protein often mutated in lipodystrophies. Here, we show that the yeast Seipin Sei1 and its partner Ldb16 also promote the storage of other NL in LDs. Importantly, this role of Sei1/Ldb16 is evolutionarily conserved as expression of human-Seipin restored normal SE-containing LDs in yeast Seipin mutants. As in the case of TAG, the formation of SE-containing LDs requires interactions between hydroxyl-residues in human Seipin or yeast Ldb16 with NL carboxyl esters. These findings provide a universal mechanism for Seipin-mediated LD formation and suggest a model for how Seipin distinguishes NLs from aliphatic phospholipid acyl chains in the center of the membrane bilayer.

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“…Similarly, the composition of the neutral core can vary substantially depending on the predominating substrate used to build LDs, especially in particular cell types such as macrophages: the LD can be formed predominantly from cholesterol esters or triacylglycerides; this can have a profound impact on protein association, usage dynamics and even ultrastructural organization ( Fujimoto and Parton, 2011 ; Mejhert et al, 2020 ). The neutral core of LDs can also contain esters of other lipid species such as the ether monoalk (en)yl diacylglycerol ( Bartz et al, 2007 ) or retinol esters ( Molenaar et al, 2021 ); while their biogenesis is regulated by distinct mechanisms, we have a limited understanding of their functional particularities.…”

Section: Future Directionsmentioning

confidence: 99%

Insights Into the Biogenesis and Emerging Functions of Lipid Droplets From Unbiased Molecular Profiling Approaches

Sánchez-Álvarez

Pozo

Bosch

et al. 2022

Front. Cell Dev. Biol.

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Lipid droplets (LDs) are spherical, single sheet phospholipid-bound organelles that store neutral lipids in all eukaryotes and some prokaryotes. Initially conceived as relatively inert depots for energy and lipid precursors, these highly dynamic structures play active roles in homeostatic functions beyond metabolism, such as proteostasis and protein turnover, innate immunity and defense. A major share of the knowledge behind this paradigm shift has been enabled by the use of systematic molecular profiling approaches, capable of revealing and describing these non-intuitive systems-level relationships. Here, we discuss these advances and some of the challenges they entail, and highlight standing questions in the field.

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Retinyl esters form lipid droplets independently of triacylglycerol and seipin

Cited by 25 publications

References 64 publications

Contrasting effects of reduced phosphatidylcholine synthesis in absence of seipin: embryonic lethality goes down while lipid droplets get even larger

Contrasting effects of reduced phosphatidylcholine synthesis in absence of seipin: embryonic lethality goes down while lipid droplets get even larger

Seipin concentrates distinct neutral lipids via interactions with their acyl chain carboxyl esters

Insights Into the Biogenesis and Emerging Functions of Lipid Droplets From Unbiased Molecular Profiling Approaches

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