New insights into Berardinelli-Seip congenital lipodystrophy type 2

Berardinelli-Seipin congenital lipodystrophy type 2 (BSCL2), the most severe form of lipodystrophy that results in the loss of almost all subcutaneous fat, is caused by mutations in the BSCL2/seipin gene. Seipin is an integral protein of the endoplasmic reticulum (ER) that has been shown to play an important role in lipid droplet homeostasis and lipid storage.

In seipin-deficient cells, inferior lipid droplet biogenesis causes abnormal lipid partitioning along with aberrant extra-large lipid droplets, which is also observed in phosphatidylcholine (PH)-deficient cells. In addition to the cellular lipid droplet defect, seipin deficiency also causes a variety of physiological defects such as fatty liver, diabetes, mental retardation and sperm abnormalities. It is unclear whether all of these defects are due to defective lipid droplet homeostasis or other mechanisms.

A study by scientists from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, demonstrates that deficiency in the B12-one-carbon cycle-phosphatidylcholine (PC) axis reduces embryonic mortality but exacerbates the lipid droplet defect in nematode seipin mutants. C. elegans. This finding suggests that some of the physiological defects of BSCL2 may be independent of lipid droplet abnormalities. The study was published in Vital metabolism.

In this study, the authors used the C. elegans BSCL2 seip-1 model. seip-1 mutants exhibit both embryonic lethality and a lipid droplet abnormality. To understand how seip-1 affects embryogenesis, they performed a genetic screen to identify suppressors of the embryonic lethal phenotype in seip-1 mutants. They identified the transcription factor nhr-114 and spin-4, a putative transporter of the core facilitator family, as suppressors of seip-1 embryonic lethality. Both nhr-114 and spin-4 act on the same B12-one carbon cycle-PC pathway.

PC levels were significantly reduced by nhr-114 and spino-4 mutations in seip-1 mutants. These results indicated that nhr-114 and spin-4 mutations suppress the embryonic lethality of seip-1 through PC deficiency. Accordingly, mutation of pcyt-1 , which encodes the rate-limiting enzyme for PC synthesis, also suppresses the embryonic lethality of seip-1 mutants.

To investigate the underlying mechanism of PC deficiency suppression of seip-1 embryonic lethality, the authors further examined the genetic interaction between seip-1 and a panel of flippases and scramblelases that shape the phospholipid bilayer of the membrane.

Interestingly, knockdown of the C. elegans homologue of human VMP1, an ER-resident phospholipid scramblelase, ameliorated the embryonic lethality of seip-1 and enhanced the suppressive effect of the suppressors. These results indicate that ER phospholipid homeostasis is important for the embryonic development of seip-1 mutants.

To delineate the relationship between the roles of seipin in cellular lipid droplet homeostasis and physiological functions, the authors examined the effect of PC deficiency on lipid droplet homeostasis in seip-1 mutants. Notably, PC-deficient mutations further increased the number of ultralarge lipid droplets in seip-1 mutants.

Taken together, while PC deficiency suppresses embryonic lethality, it exacerbates the large lipid droplet phenotype in seip-1 mutants. These results indicate that seipin can regulate lipid droplet embryogenesis and homeostasis through different mechanisms.

Suppression of the physiological phenotype of seipin deficiency by PC depletion is somewhat unexpected, as both result in a similar cellular lipid droplet phenotype. The next aim will be to examine the rescue effect of reducing PC synthesis or VMP1 activity in vertebrate BSCL2 models. This study also highlights the importance of distinguishing between cellular phenotypes and physiological phenotypes in disease models.

Courtesy of Higher Education Press