CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development

Abstract

Lipid droplets (LDs) are highly dynamic organelles that play a central role in mammalian energy storage. LDs are also involved in many cellular functions, including protein storage and degradation, and membrane and lipid trafficking (1-4). Each LD contains a hydrophobic neutral lipid core enclosed by a phospholipid monolayer (5). In mammals, the lipid core comprises mainly triacylglycerols (TAGs) and cholesteryl esters. The molecular events underlying the biogenesis of LDs remain to be determined (6). While several models have been proposed, the prevailing view is that LDs originate and bud from the endoplasmic reticulum (ER), followed by expansion and maturation (7). A recent study suggests that the fat storage-inducing transmembrane proteins are required for proper budding of LDs from the ER (8). The growth of LDs is not fully understood, as the size of LDs varies within different tissues and even within the same cell type (9). Recent studies have established the Cide family proteins, Cidec/FSP27 in particular, as key regulators of LD growth/fusion in adipocytes (10, 11). Phospholipids, especially phosphatidylcholine (PC) and phosphatidic acid (PA), also appear to be important regulators of LD growth and proliferation, as a decrease in PC or an increase in PA can both result in the formation of giant or "supersized" LDs (1, 9, 12, 13). LDs can also grow by lipid synthesis in situ, as TAG synthesis enzymes can relocate from the ER to the LD surface to mediate LD growth (14). Despite these important findings, Abstract 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 (DAG) synthases (CDSs), 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 3T3-L1 preadipocytes, whereas depleting CDS2 had a moderate inhibitory effect on adipocyte differentiation. The levels of many 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.-Qi, Y., T.

SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase

“…Phospholipids were extracted from microsomes isolated from yeast or mammalian cells, subjected to high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS) and analyzed using Lipid Search software as described ( Qi et al, 2016 ; Fei et al, 2011c ).…”

The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

“…CDS1 is a key enzyme in this branching point where they convert PA into CDP-DAG for phosphatidylinositol (PI) and phsophatidylglycerol (PG) synthesis. Knocking down CDS1 increased the amount of PA, triggered the formation of giant lipid droplets and reduce the amount of PI and PG [37]. We observed that activation of VDR in human hepatocytes upregulated CDS1.…”

Cloning, characterization, and expression features of chicken CDS2 splicing variants

“…CDS has been linked with lipid metabolism [1,2,15,20,21], with a stronger effect on phosphatidic acid levels. CDS2 de ciency (while not CDS1) could impair the maturation of initial lipid droplets in cultured mammalian cells [21].…”

“…CDP-diacylglycerol synthases (CDSs) are critical enzymes that catalyze the synthesis of cytidine diphosphate diacylglycerol (CDP-DAG) from phosphatidic acid to produce phospholipids such as phosphatidylinositol, phosphatidylglycerol, and cardiolipin [1,2]. The gene encoding CDS was rst cloned from Escherichia coli in 1985 [3], while the rst eukaryotic CDS was cloned from Drosophila in 1995, which shares 31% amino acid similarity with bacterial CDS [4].…”

“…Recent reports have revealed that the CDS gene is involved in lipid metabolism [1,2,15,20,21], and mammalian CDS1 and CDS2 regulate lipid droplets through distinct mechanisms [21]. Human CDS1 and CDS2 can create different CDP-DAG pools; CDS2 is selective for acyl chains at the sn-1 and sn-2 positions [22].…”