Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesis and lipid droplet expansion but whose molecular function remains obscure. Here, we identify physical and functional interactions between SEIPIN and microsomal isoforms of glycerol-3-phosphate acyltransferase (GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss. Overexpression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin-/- mouse preadipocytes partially restored adipogenesis. These data identify SEIPIN as an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2 patients.

FTY720, a sphingosine analog, is a novel immunosuppressant currently undergoing multiple clinical trials for the prevention of organ transplant rejection and treatment of various autoimmune disease...

Lipotoxic stress‐induced β‐cell death (lipotoxicity) is recognized as a key contributor to the development of type 2 diabetes mellitus (T2DM). The current study reports a critical role of sphingosine kinase 1 (SphK1) in β‐cell survival under lipotoxic conditions. In an attempt to investigate the role of SphK1 in lipotoxicity in vivo, we fed Sphk1 ^–/– and wild‐type (WT) mice with a high‐fat diet (HFD) or normal chow diet. Remarkably, while HFD‐fed WT mice developed glucose intolerance and compensatory hyperinsulinemia, all HFD‐fed Sphk1 ^–/– mice manifested evident diabetes, accompanied by a nearly 3‐fold reduction in insulin levels compared with the WT mice. Pancreatic β‐cell mass was increased by 140% in HFD‐fed WT mice but decreased to 50% in HFD‐fed Sphk1 ^–/– mice, in comparison with the chow diet control groups, respectively. Accordingly, by blocking the enzyme activity, expression of a dominant negative form of SphK1 markedly promoted palmitate‐induced cell death in MIN6 and INS‐1 β‐cell lines. Moreover, primary islets isolated from Sphk1 ^–/– mice exhibited higher susceptibility to lipotoxicity than WT controls. Of note, sphingosine 1‐phosphate (S1P) profoundly abrogated lipotoxicity in β cells or the cells lacking SphK1 activity and Sphk1 ^–/– islets, highlighting a pivotal role of S1P in β‐cell survival under lipotoxic conditions. These findings could suggest a new therapeutic strategy for preventing β‐cell death and thus the onset of T2DM.—Qi, Y., Chen, J., Lay, A., Don, A., Vadas, M., Xia, P., Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic β‐cell death in diet‐induced obese mice. FASEB J. 27, 4294–4304 (2013). www.fasebj.org

The expansion of lipid droplets (LDs) and the differentiation of preadipocytes are two important aspects of mammalian lipid storage. In this study, we examined the role of CDP-diacylglycerol (CDP-DAG) synthases (CDS), encoded by CDS1 and CDS2 genes in mammals, in lipid storage. CDS enzymes catalyze the formation of CDP-DAG from phosphatidic acid (PA). Knocking down either CDS1 or CDS2 resulted in the formation of giant or supersized LDs in cultured cells. Moreover, depleting CDS1 almost completely blocked the differentiation of 3T3L1 preadipocytes, whereas depleting CDS2 had a moderate inhibitory effect on adipocyte differentiation. The levels of many phosphatidic acid (PA) species were significantly increased upon knocking down CDS1. In contrast, only a small number of PA species were increased upon depleting CDS2. Importantly, the amount of PA in the endoplasmic reticulum was dramatically increased upon knocking down CDS1 or CDS2. Our results suggest that the changes in PA level and localization may underlie the formation of giant LDs as well as the block in adipogenesis in CDS-deficient cells. We have therefore identified CDS1 and CDS2 as important novel regulators of lipid storage, and these results highlight the crucial role of phospholipids in mammalian lipid storage.