DAG tales: the multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling

Abstract

The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a constant and controlled availability. Interestingly, DAG species are versatile in their chemical structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biological properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochemistry and their impact on cellular metabolism and signaling. Further, we describe intracellular DAG turnover and its stereochemistry in a 3-pool model to illustrate the spatial and stereochemical separation and hereby the diversity of cellular DAG metabolism.

Keywords: Acyltransferase; Hydrolase; Insulin; Kinase; Lipase.

Fig. 1

Schematic depiction of the different forms of isomerism of diacylglycerol. Diacylglycerols feature different forms of isomerism and can differ either in constitutional (structural) or spatial (stereo) conformation. For detailed explanation see text

Fig. 2

R/S nomenclature of diacylglycerol (DAG) enantiomers according to Cahn–Ingold–Prelog convention. sn-1,2 DAG represents the S-configuration whereas sn-2,3 DAG represents the R-configuration

Fig. 3

Catabolic and anabolic reactions leading to the formation of diacylglycerol. Different stereo/regioisomers of diacylglycerols are generated by the hydrolysis of either triacylglycerol (lipase) or phospholipids (phospholipase), and are product of sphingomyelin synthesis (transferase reaction). Furthermore, diacylglycerol is the product of the dephosphorylation of phosphatidic acid (phosphatase) and of the esterification of monoacylglycerol by acyltransferases. Carbon atoms of the glycerol backbone are depicted as filled (esterified) or open (unesterified) circles. Phosphate group, phosphate head group, and fatty acids are depicted as red circle, open rhomb, and dash, respectively

Fig. 4

Intracellular enzyme classes involved in diacylglycerol utilization. Different isoforms of diacylglycerol display substrates for several enzyme classes, including transferases, kinases, and lipases. Carbon atoms of the glycerol backbone are depicted as filled (esterified) or open (unesterified) circles. Phosphate group, phosphate head group, and fatty acids are depicted as red circle, open rhomb, and dash, respectively

Fig. 5

Intracellular pathway of insulin signaling and proposed impairment by DAG. a Insulin binds to insulin receptor that activates IRS. This leads to the activation of PI3K and further downstream signaling which finally triggers the translocation of GLUT4 to the plasma membrane and enables glucose uptake. b sn-1,2 DAG activates novel and conventional PKC isoforms which phosphorylate IRS. This event inhibits downstream effector signaling and GLUT4-dependent glucose uptake. DAG diacylglycerol, GLUT4 glucose transporter 4, IRS insulin receptor substrate, P phosphorylation, PI3K phosphoinositide-3-kinase, PKC protein kinase C

Fig. 6

“3-Pool” compartmentation model of intracellular diacylglycerols. Intracellular diacylglycerols differ in their stereo/regio conformation, compartmentation, and generating/consuming enzymes. For detailed description see text. ATGL adipose triglyceride lipase, CGI-58 comparative gene identification-58, CEPT CDP-ethanolamine/choline:1,2-diacylglycerol ethanolaminephosphotransferase CPT, CDP-choline:1,2-diacylglycerol ethanolaminephosphotransferase, DAG diacylglycerol, DAGL DAG lipase, DGAT DAG-O-acyltransferase, DGK DAG kinase, EPT CDP-ethanolamine:1,2-diacylglycerol ethanolaminephosphotransferase, HSL hormone-sensitive lipase, MAG monoacylglycerol, MGAT monoacylglycerol-O-acyltransferase, PA phosphatidic acid, PAP PA phosphohydrolase/lipin, PC phosphatidylcholine, PL phospholipid, PLC phospholipase C, SMS(r) sphingomyelin synthase (related), TAG triacylglycerol