Lipid Messenger, Diacylglycerol, and its Regulator, Diacylglycerol Kinase, in Cells, Organs, and Animals: History and Perspective

Goto, Kaoru; Hozumi, Yasukazu; Nakano, Tomoyuki; Saino-Saito, Sachiko; Martelli, Alberto M.

doi:10.1620/tjem.214.199

Cited by 36 publications

(37 citation statements)

References 124 publications

(115 reference statements)

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“…It was proposed that because different PA-producing enzymes are located on or within specific subcellular organelles, the PA molecules produced by these enzymes might function differently because of their cellular compartmentalization (1,26,41). PA derived from GPAT (via AGPAT) is produced at the outer mitochondrial membrane, at the lipid droplet, or at the ER surface (26,42,43); the PA produced by PLD1 is present in the Golgi and the nucleus (44); and DGK produces PA at the plasma membrane, ER, and nucleus (45). However, because our previous and current data show that each of three different catalytic pathways, GPAT/AGPAT, PLD, and DGK, provides PA that inhibits insulin signaling to Akt, the ability of PA to disrupt insulin signaling suggests that the effect of the PA may be unrelated to its source.…”

Section: Discussionmentioning

confidence: 99%

Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

Zhang

Hwarng

Cooper

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism underlying the association of triacylglycerol storage and insulin resistance is unclear. Results: Increasing phosphatidic acid (PA) in primary hepatocytes via de novo synthesis or action of phospholipase D or diacylglycerol kinase-disrupts insulin signaling. Conclusion: PA derived from different sources inhibits insulin signaling. Significance: Increases in hepatocyte PA may mechanistically link lipid storage and insulin action.

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Section: Discussionmentioning

confidence: 99%

Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

Zhang

Hwarng

Cooper

et al. 2015

Journal of Biological Chemistry

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“…In considering other phosphoinositide metabolites, the glycerophosphoinositols fall among the active products of phospholipid metabolism that arise from activation of phospholipase A 2 (PLA 2 ), which also include the monoacylglycerols, the lysophospholipids, and the various products of arachidonic acid metabolism [9][10][11].…”

Section: Lipid-derived Messengersmentioning

confidence: 99%

The glycerophosphoinositols: cellular metabolism and biological functions

Corda

Zizza

Varone

et al. 2009

Cell. Mol. Life Sci.

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The glycerophosphoinositols are cellular products of phospholipase A(2) and lysolipase activities on the membrane phosphoinositides. Their intracellular concentrations can vary upon oncogenic transformation, cell differentiation and hormonal stimulation. Specific glycerophosphodiester phosphodiesterases are involved in their catabolism, which, as with their formation, is under hormonal regulation. With their mechanisms of action including modulation of adenylyl cyclase, intracellular calcium levels, and Rho-GTPases, the glycerophosphoinositols have diverse effects in multiple cell types: induction of cell proliferation in thyroid cells; modulation of actin cytoskeleton organisation in fibroblasts; and reduction of the invasive potential of tumour cell lines. More recent investigations include their effects in inflammatory and immune responses. Indeed, the glycerophosphoinositols enhance cytokine-dependent chemotaxis in T-lymphocytes induced by SDF-1alpha-receptor activation, indicating roles for these compounds as modulators of T-cell signalling and T-cell responses.

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“…Diacylglycerol kinases (DGK 3 ; EC 2.7.1.107) are a diverse family of lipid kinases that catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA) using ATP as a phosphate donor (1)(2)(3)(4)(5)(6)(7)(8). DAG is a lipid second messenger whose importance in cell signaling is well established (9).…”

mentioning

confidence: 99%

Diacylglycerol Kinase ϵ Is Selective for Both Acyl Chains of Phosphatidic Acid or Diacylglycerol

Lung

Shulga

Ivanova

et al. 2009

Journal of Biological Chemistry

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The phosphatidylinositol (PI) cycle mediates many cellular events by controlling the metabolism of many lipid second messengers. Diacylglycerol kinase ⑀ (DGK⑀) has an important role in this cycle. DGK⑀ is the only DGK isoform to show inhibition by its product phosphatidic acid (PA) as well as substrate specificity for sn-2 arachidonoyl-diacylglycerol (DAG). Here, we show that this inhibition and substrate specificity are both determined by selectivity for a combination of the sn-1 and sn-2 acyl chains of PA or DAG, respectively, preferring the most prevalent acyl chain composition of lipids involved specifically in the PI cycle, 1-stearoyl-2-arachidonoyl. Although the difference in rate for closely related lipid species is small, there is a significant enrichment of 1-stearoyl-2-arachidonoyl PI because of the cyclical nature of PI turnover. We also show that the inhibition of DGK⑀ by PA is competitive and that the deletion of the hydrophobic segment and cationic cluster of DGK⑀ does not affect its selectivity for the acyl chains of PA or DAG. Thus, this active site not only recognizes the lipid headgroup but also a combination of the two acyl chains in PA or DAG. We propose a mechanism of DGK⑀ regulation where its dual acyl chain selectivity is used to negatively regulate its enzymatic activity in a manner that ensures DGK⑀ remains committed to the PI turnover cycle. This novel mechanism of enzyme regulation within a signaling pathway could serve as a template for the regulation of enzymes in other pathways in the cell.Diacylglycerol kinases (DGK 3 ; EC 2.7.1.107) are a diverse family of lipid kinases that catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA) using ATP as a phosphate donor (1-8). DAG is a lipid second messenger whose importance in cell signaling is well established (9). DAG is generated through the catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) by the various isoforms of phospholipase C in response to cell stimulation by various agonists such as growth factors, cytokines, and hormones (9, 10). The diverse range of effectors of DAG allows it to modulate a large variety of cellular events, resulting in its broad effects on the cell. Of these effectors, DAG is most known as an allosteric activator of protein kinase C (11-14). DAG also activates other effectors such as Ras-guanyl nucleotide-releasing protein (11) and the transient receptor potential channel 2 (15). Furthermore, DAG is involved in the recruitment of chimerins (16), Munc13, and protein kinase D to the membrane (11). Because DAG is such an important signaling molecule, there must be tight regulation of its concentration. The DGK-catalyzed phosphorylation of DAG to PA serves as one pathway for the attenuation of the pleiotropic effects of DAG.Although the reaction catalyzed by DGK attenuates the effects of DAG, the product of the reaction, PA, is also a lipid second messenger that has its own range of effects on the cell through its own set of diverse effectors. For instance, PA ...

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Lipid Messenger, Diacylglycerol, and its Regulator, Diacylglycerol Kinase, in Cells, Organs, and Animals: History and Perspective

Cited by 36 publications

References 124 publications

Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

The glycerophosphoinositols: cellular metabolism and biological functions

Diacylglycerol Kinase ϵ Is Selective for Both Acyl Chains of Phosphatidic Acid or Diacylglycerol

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