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Metabolism of Acylglycerols & Sphingolipids

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Metabolism of Acylglycerols & Sphingolipids ch24.qxd 2/13/2003 3:28 PM Page 197 Metabolism of Acylglycerols & Sphingolipids 24 Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc BIOMEDICAL IMPORTANCE possess glycerol kinase, found in significant amounts in liver, kidney, intestine, brown adipose tissue, and Acylglycerols constitute the majority of lipids in the lactating mammary gland. body. Triacylglycerols are the major lipids in fat de- posits and in food, and their roles in lipid transport and storage and in various diseases such as obesity, diabetes, TRIACYLGLYCEROLS & and hyperlipoproteinemia will be described in subse- PHOSPHOGLYCEROLS ARE FORMED BY quent chapters. The amphipathic nature of phospho- lipids and sphingolipids makes them ideally suitable as ACYLATION OF TRIOSE PHOSPHATES the main lipid component of cell membranes. Phos- The major pathways of triacylglycerol and phosphoglyc- pholipids also take part in the metabolism of many erol biosynthesis are outlined in Figure 24–1. Impor- other lipids. Some phospholipids have specialized func- tant substances such as triacylglycerols, phosphatidyl- tions; eg, dipalmitoyl lecithin is a major component of choline, phosphatidylethanolamine, phosphatidylinositol, lung surfactant, which is lacking in respiratory distress and cardiolipin, a constituent of mitochondrial mem- syndrome of the newborn. Inositol phospholipids in the branes, are formed from glycerol-3-phosphate. Significant cell membrane act as precursors of hormone second branch points in the pathway occur at the phosphati- messengers, and platelet-activating factor is an alkyl- date and diacylglycerol steps. From dihydroxyacetone phospholipid. Glycosphingolipids, containing sphingo- phosphate are derived phosphoglycerols containing an sine and sugar residues as well as fatty acid and found in ether link (COC), the best-known of which the outer leaflet of the plasma membrane with their are plasmalogens and platelet-activating factor (PAF). oligosaccharide chains facing outward, form part of the Glycerol 3-phosphate and dihydroxyacetone phosphate glycocalyx of the cell surface and are important (1) in are intermediates in glycolysis, making a very important cell adhesion and cell recognition; (2) as receptors for connection between carbohydrate and lipid metabo- bacterial toxins (eg, the toxin that causes cholera); and lism. (3) as ABO blood group substances. A dozen or so gly- colipid storage diseases have been described (eg, Gaucher’s disease, Tay-Sachs disease), each due to a ge- netic defect in the pathway for glycolipid degradation in the lysosomes. Glycerol 3-phosphate Dihydroxyacetone phosphate HYDROLYSIS INITIATES CATABOLISM OF TRIACYLGLYCEROLS Phosphatidate Plasmalogens PAF Triacylglycerols must be hydrolyzed by a lipase to their constituent fatty acids and glycerol before further catab- olism can proceed. Much of this hydrolysis (lipolysis) Diacylglycerol Cardiolipin Phosphatidylinositol occurs in adipose tissue with release of free fatty acids into the plasma, where they are found combined with serum albumin. This is followed by free fatty acid up- Phosphatidylcholine Triacylglycerol Phosphatidylinositol take into tissues (including liver, heart, kidney, muscle, Phosphatidylethanolamine 4,5-bisphosphate lung, testis, and adipose tissue, but not readily by brain), where they are oxidized or reesterified. The uti- Figure 24–1. Overview of acylglycerol biosynthesis. lization of glycerol depends upon whether such tissues (PAF, platelet-activating factor.) 197 ch24.qxd 2/13/2003 3:28 PM Page 198 ATP ADP NAD+ NADH + H+ H 2C OH H 2C OH H 2C OH HO C H HO C H CO Glycolysis H 2C OH GLYCEROL KINASE H 2C O P GLYCEROL- H 2C O P 3-PHOSPHATE Glycerol sn -Glycerol Dihydroxyacetone DEHYDROGENASE 3-phosphate phosphate Acyl-CoA (mainly saturated) GLYCEROL- 2 3-PHOSPHATE ACYLTRANSFERASE CoA O H 2C O C R1 HO CH H 2C OH H 2C O P R2 C O C H 1-Acylglycerol- 3-phosphate O H 2C OH (lysophosphatidate) 2-Monoacylglycerol Acyl-CoA (usually unsaturated) 1-ACYLGLYCEROL- 3-PHOSPHATE ACYLTRANSFERASE Acyl-CoA 1 CoA MONOACYLGLYCEROL ACYLTRANSFERASE O (INTESTINE) H 2C O C R1 CoA R2 C O C H O H 2C O P 1,2-Diacylglycerol phosphate (phosphatidate) Choline H 2O CTP ATP PHOSPHATIDATE CDP-DG PHOSPHOHYDROLASE SYNTHASE CHOLINE KINASE P 1 PP 1 ADP O O Phosphocholine H 2C O C R1 H 2C O C R1 CTP R2 C O C H R2 C O C H CTP: PHOSPHOCHOLINE O H 2COH O H 2C O P P CYTIDYL 1,2-Diacylglycerol TRANSFERASE Cytidine CDP-diacylglycerol Cardiolipin PP1 CDP-choline Acyl-CoA Inositol CDP-CHOLINE: DIACYLGLYCEROL DIACYLGLYCEROL PHOSPHATIDYL- PHOSPHOCHOLINE ACYLTRANSFERASE INOSITOL SYNTHASE TRANSFERASE CoA CMP CMP ATP ADP O O O KINASE O H 2C O C R1 H 2C O C R1 H 2C O C R1 H 2C O C R1 R2 C O C H R2 C O C H O R2 C O C H R2 C O C H O HC2 O P O HC2 O C R3 O HC2 O P O HC2 O P Inositol P Triacyglycerol Choline Inositol Phosphatidylinositol 4-phosphate Phosphatidylinositol Phosphatidylcholine ATP PHOSPHATIDYLETHANOLAMINE N-METHYLTRANSFERASE (–CH3)3 KINASE Phosphatidylethanolamine Serine CO2 ADP O H 2C O C R1 Phosphatidylserine Ethanolamine R2 C O C H Figure 24–2 . Biosynthesis of triacylglycerol and phospholipids. O HC2 O P Inositol P (᭺1 , Monoacylglycerol pathway; ᭺2 , glycerol phosphate pathway.) P Phosphatidylethanolamine may be formed from ethanolamine by a Phosphatidylinositol 4,5-bisphosphate pathway similar to that shown for the formation of phosphatidyl- choline from choline. ch24.qxd 2/13/2003 3:28 PM Page 199 METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 199 Phosphatidate Is the Common Precursor from phosphatidylglycerol, which in turn is synthesized in the Biosynthesis of Triacylglycerols, from CDP-diacylglycerol (Figure 24–2) and glycerol Many Phosphoglycerols, & Cardiolipin 3-phosphate according to the scheme shown in Figure 24–3. Cardiolipin, found in the inner membrane of Both glycerol and fatty acids must be activated by ATP mitochondria, is specifically required for the function- before they can be incorporated into acylglycerols. ing of the phosphate transporter and for cytochrome Glycerol kinase catalyzes the activation of glycerol to oxidase activity. sn-glycerol 3-phosphate. If the activity of this enzyme is absent or low, as in muscle or adipose tissue, most of the glycerol 3-phosphate is formed from dihydroxyace- B. BIOSYNTHESIS OF GLYCEROL ETHER PHOSPHOLIPIDS tone phosphate by glycerol-3-phosphate dehydrogen- This pathway is located in peroxisomes. Dihydroxyace- ase (Figure 24–2). tone phosphate is the precursor of the glycerol moiety of glycerol ether phospholipids (Figure 24–4). This A. BIOSYNTHESIS OF TRIACYLGLYCEROLS compound combines with acyl-CoA to give 1-acyldihy- Two molecules of acyl-CoA, formed by the activation droxyacetone phosphate. The ether link is formed in of fatty acids by acyl-CoA synthetase (Chapter 22), the next reaction, producing 1-alkyldihydroxyacetone combine with glycerol 3-phosphate to form phosphati- phosphate, which is then converted to 1-alkylglycerol date (1,2-diacylglycerol phosphate). This takes place in 3-phosphate. After further acylation in the 2 position, two stages, catalyzed by glycerol-3-phosphate acyl- the resulting 1-alkyl-2-acylglycerol 3-phosphate (analo- transferase and 1-acylglycerol-3-phosphate acyltrans- gous to phosphatidate in Figure 24–2) is hydrolyzed to ferase. Phosphatidate is converted by phosphatidate give the free glycerol derivative. Plasmalogens, which phosphohydrolase and diacylglycerol acyltransferase comprise much of the phospholipid in mitochondria, to 1,2-diacylglycerol and then triacylglycerol. In intesti- are formed by desaturation of the analogous 3-phos- nal mucosa, monoacylglycerol acyltransferase con- phoethanolamine derivative (Figure 24–4). Platelet- verts monoacylglycerol to 1,2-diacylglycerol in the activating factor (PAF) (1-alkyl-2-acetyl-sn-glycerol-3- monoacylglycerol pathway. Most of the activity of phosphocholine) is synthesized from the corresponding these enzymes resides in the endoplasmic reticulum of 3-phosphocholine derivative. It is formed by many the cell, but some is found in mitochondria. Phosphati- blood cells and other tissues and aggregates platelets at date phosphohydrolase is found mainly in the cytosol, concentrations as low as 10−11 mol/L. It also has hy- but the active form of the enzyme is membrane-bound. potensive and ulcerogenic properties and is involved in In the biosynthesis of phosphatidylcholine and a variety of biologic responses, including inflammation, phosphatidylethanolamine (Figure 24–2), choline or chemotaxis, and protein phosphorylation. ethanolamine must first be activated by phosphoryla- tion by ATP followed by linkage to CTP. The resulting CDP-choline or CDP-ethanolamine reacts with 1,2-di- acylglycerol to form either phosphatidylcholine or CDP-Diacyl- sn-Glycerol phosphatidylethanolamine, respectively. Phosphatidyl- glycerol 3-phosphate serine is formed from phosphatidylethanolamine di- rectly by reaction with serine (Figure 24–2). Phos- CMP phatidylserine may re-form phosphatidylethanolamine by decarboxylation. An alternative pathway in liver en- Phosphatidylglycerol phosphate ables phosphatidylethanolamine to give rise directly to H2O phosphatidylcholine by progressive methylation of the ethanolamine residue. In spite of these sources of choline, it is considered to be an essential nutrient in Pi many mammalian species, but this has not been estab- lished in humans. Phosphatidylglycerol The regulation of triacylglycerol, phosphatidyl- choline, and phosphatidylethanolamine biosynthesis is driven by the availability of free fatty acids. Those that escape oxidation
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  • Supplementary Table 1
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