Reduced phosphatidylcholine synthesis suppresses the embryonic lethality of seipin deficiency.

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 , the seipin ortholog, causes embryonic lethality and lipid droplet abnormality. We uncover and as two suppressors of embryonic lethality. Mechanistically, and act in the "B12-one-carbon cycle-phosphatidylcholine (PC)" axis, and reducing PC synthesis suppresses the embryonic lethality of mutants. Conversely, PC deficiency enhances the lipid droplet abnormality of mutants. The suppression of embryonic lethality by PC reduction requires polyunsaturated fatty acid. In addition, the suppression is enhanced by the knockdown of phospholipid scramblase . Therefore, seipin and PC 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.