1,3-diacylglycerols

HIROYUKIWATANABE AND NOBORU MATSUO Kao Corp, TocfUgi, Japan 

Obesity is a growing problem worldwide, not only in industrialized countries, but also in urban areas of developing countries. According to World Health Organization (WHO) statistics, the number of obese adults increased from 200 million in 1995 to over 300 miUion in 2000. 

Obesity is associated with a number of health risks, such as heart disease, diabetes mellitus, hypertension, gallbladder disease, and some types of cancer (Carey etal., 1997 Lamon-Fava eta/., 1996 Rimm eta/., 1995 Mokdad eta/., 2001). The importance of reducing body fat accumulation in the prevention of lifestyle-related diseases has been noted by many experiments and surveys. Clinical studies have suggested that weight loss in the range of 5-10% of initial weight can confer significant reductions in obesity-related disorders. 

Functional foods and materials that improve fat metabolism have been extensively studied. Diets for weight loss generally recommend restricting intakes of energy, total fats, and saturated fats. In contrast, we have focused on the nature of the glycerol esters rather than on the fatty acid composition of oils, and have found that DAG, particularly in the 1,3-isoform, have metabolic characteristics distinct from those of TAG and are less likely to become stored body fat. A cooking oil product containing at least 80% (w/w) DAG has been on the market in Japan as a food for specified health use (FOSHU) since 1999. In this chapter, the nutritional characteristics and beneficial health effects of DAG observed in several clinical studies are outlined and possible mechanisms for these effects are discussed. 

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Hydrolysis of the phosphate ester function of the phosphatidic acid gives a diacylglycerol which then reacts with a third acyl coenzyme A molecule to produce a triacylglycerol... 

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

One important phospholipid is phosphatidylcholine, also called lecithin. Phosphatidylcholine is a mixture of diesters of phosphoric acid. One estei function is derived from a diacylglycerol, whereas the other is a choline [—OCH2CH2N(CH3)3] unit. 

Olid carbon is asymmetric. The various acylglycerols are normally soluble in benzene, chloroform, ether, and hot ethanol. Although triacylglycerols are insoluble in water, mono- and diacylglycerols readily form organized structures in water (discussed later), owing to the polarity of their free hydroxyl groups. 

Eukaryotes Synthesize Glycerolipids from CDP-Diacylglycerol or Diacylglycerol... 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

FIGURE 25.19 Diacylglycerol and CDP-diacylglycerol are the principal precursors of glycerolipids in eukaryotes. Phosphatidylethanolamine and phosphatidylcholine are formed by reaction of diacylglycerol with CDP-ethanolamine or CDP-choline, respectively. 

FIGURE 25.20 Triacylglycerols are formed primarily by the action of acyltransferases on mono- and diacylglycerol. Acyltransferase in E. coli is an integral membrane protein (83 kD) and can utilize either fatty acyl-CoAs or acylated acyl carrier proteins as substrates. It shows a particular preference for palmitoyl groups. Eukaryotic acyltransferases nse only fatty acyl-CoA molecnles as substrates. 

FIGURE 25.22 CDP-diacylglycerol is a precursor of phosphaddylinositol, phosphaddyl-glycerol, and cardiolipin in eukaryotes. 

Eicosanoids, so named because they are all derived from 20-carbon fatty acids, are ubiquitous breakdown products of phospholipids. In response to appropriate stimuli, cells activate the breakdown of selected phospholipids (Figure 25.27). Phospholipase Ag (Chapter 8) selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are unsaturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacyl-glycerols) and diacylglycerol lipase (which releases fatty acids). 

The tetrahedral intermediate expels a diacylglycerol as the leaving group and produces an acyl enzyme. The step is catalyzed by a proton transfer from histidine to make the leaving group a neutral alcohol. 

FIGURE 2.7 Production of second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) through activation of the enzyme phospholipase C. This enzyme is activated by the a- subunit of Gq-protein and also by Py subunits of Gj-protein. IP3 stimulates the release of Ca2+ from intracellular stores while DAG is a potent activator of protein kinase C. 

Diacylglycerol is glycerol esterified to two fatty acids at the sn-1 and sn-2 positions. It is a membrane-embedded product of phospholipase C action and an activator of protein kinase C. It is also an intermediate in the biosynthesis of triacylglycerol, phosphatidyletha-nolamine and phosphatidylcholine. 

Natural products from the Euphorbiaccae family of plants that mimic the effects of diacylglycerol by binding the Cl domain of proteins such as PKC. 

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