Diacylglycerol Kinase Delta Promotes Lipogenesis

Abstract

We have studied the relationship between diacylglycerol kinase delta (DGKδ) and lipogenesis. There is a marked increase in the expression of DGKδ during the differentiation of 3T3-L1 cells to adipocytes, as well as in the synthesis of neutral and polar lipids. When 3T3-L1 undifferentiated fibroblasts are transfected to express DGKδ there is increased triglyceride synthesis without differentiation to adipocytes. Hence, expression of DGKδ promotes lipogenesis. Lipid synthesis is decreased in DGKδ knockout mouse embryo fibroblasts, especially for lipids with shorter acyl chains and limited unsaturation. This reduction occurs for both neutral and polar lipids. These findings suggest reduced de novo lipid synthesis. This is confirmed by measuring the incorporation of glycerol into polar and neutral lipids that is higher in the wild type cells than in the DGKδ knockouts. In comparison, there was no change in lipid synthesis in DGKε knockout mouse embryo fibroblasts. We also demonstrate that the DGKδ knockout cells had a lower expression of acetyl-CoA carboxylase and fatty acid synthase as well as a lower degree of activation by phosphorylation of ATP citrate lyase. These three enzymes are involved in the synthesis of long chain fatty acids. Our results demonstrate that DGKδ markedly increases lipid synthesis, at least in part as a result of promoting the de novo synthesis of fatty acids.

Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics

“…In cultured preadipocytes, DGK␦ silencing caused a concomitant decrease of DAG, PA, and triglycerides (28). DGK overexpression in preadipocytes promotes lipogenesis (37), consistent with a role for DGK in lipid storage in fat cells. Skeletal muscle contains substantially less total lipid than adipocytes, so the pool of DAG and PA regulated by DGK␦ may comprise a major portion of total lipid available for storage and oxidation.…”

Diacylglycerol Kinase δ Phosphorylates Phosphatidylcholine-specific Phospholipase C-dependent, Palmitic Acid-containing Diacylglycerol Species in Response to High Glucose Levels

“…Recently, Shulga et al (37) and Lowe et al (38) reported that DGK␦ positively regulated lipid synthesis, including DG and PA, during adipocyte differentiation. However, unlike for acute high glucose stimulation, a significant preference against DG and PA was not found.…”

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

“…Once generated, PtdOH can mediate signaling events by indirect mechanisms through metabolism into other bioactive lipids such as LPA by phospholipase A (Aoki, 2004) and DAG by lipid phosphate phosphatase (Brindley, 2004). PtdOH constitutes between 2 and 6% in the cellular membranes and that accounts for about 10% of the PC content (typically 30-50% of the total glycerophospholipids, depending on the biologic source) of the membranes (Andreyev et al, 2010;Shulga et al, 2013). By comparison, LPA is typically found to be less than 1% (nanomolar quantities) (Sugiura et al, 1999;Jesionowska et al, 2014), whereas total PIP n represents less than 1% of the membrane phospholipids (Czech, 2000).…”