Lipid droplets (LDs) are conserved organelles that are crucial for proper compartmentalization of fat at the subcellular level. They serve as the primary sites for storing excess neutral fat. Recent studies have yielded mechanistic insights on the biogenesis and expansion of LDs that highlighted the crucial roles of endoplasmic reticulum (ER)-LD contacts. Nonetheless, outstanding questions remain on how these contacts are specifically established and preserved.

Here, we report that a subpopulation of lipid droplet is defined by metabolite-modulated targeting of the C. elegans seipin ortholog, SEIP-1. Mutations in seipin cause the most severe form of lipodystrophy in human. Similarly, in C. elegans, deficiency of SEIP-1 reduces the size of a subset of LDs while over-expression of...[ Read more ]

Lipid droplets (LDs) are conserved organelles that are crucial for proper compartmentalization of fat at the subcellular level. They serve as the primary sites for storing excess neutral fat. Recent studies have yielded mechanistic insights on the biogenesis and expansion of LDs that highlighted the crucial roles of endoplasmic reticulum (ER)-LD contacts. Nonetheless, outstanding questions remain on how these contacts are specifically established and preserved.

Here, we report that a subpopulation of lipid droplet is defined by metabolite-modulated targeting of the C. elegans seipin ortholog, SEIP-1. Mutations in seipin cause the most severe form of lipodystrophy in human. Similarly, in C. elegans, deficiency of SEIP-1 reduces the size of a subset of LDs while over-expression of SEIP-1 has the opposite effect. Ultrastructural analysis reveals SEIP-1 enrichment in an ER subdomain, which co-purifies with LDs. Analyses of C. elegans and bacterial genetic mutants indicate a requirement of polyunsaturated fatty acids (PUFAs) and microbial cyclopropane fatty acids (CFAs) for SEIP-1 enrichment, as confirmed by dietary supplementations. In mammalian cells, heterologously expressed SEIP-1 engages nascent lipid droplets and promotes their subsequent expansion in a conserved manner. Our results provide the first characterization of the C. elegans seipin ortholog. We propose that microbial and polyunsaturated fatty acids serve unexpected roles in regulating cellular fat storage by fostering ER-LD contacts and promoting LD diversity.