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 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 (COC), 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 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 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 resides in the 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 are preferentially converted to phos- CMP pholipids, and when this requirement is satisfied they Cardiolipin are used for triacylglycerol synthesis. (diphosphatidylglycerol) A phospholipid present in mitochondria is cardio- lipin (diphosphatidylglycerol; Figure 14–8). It is formed Figure 24–3. Biosynthesis of cardiolipin. ch24.qxd 2/13/2003 3:28 PM Page 200

200 / CHAPTER 24

NADPH O + + R2 (CH2)2 OH + H NADP Acyl-CoA H2COH H2C O C R1 H2C O (CH2)2 R2 H2C O (CH2)2 R2 O C O C O C HO C H H C O P ACYL- H C O P SYNTHASE H C O P REDUCTASE H C O P 2 TRANSFERASE 2 2 2

HOOC R1 Dihydroxyacetone 1-Acyldihydroxyacetone 1-Alkyldihydroxyacetone 1-Alkylglycerol 3-phosphate phosphate phosphate phosphate Acyl-CoA

ACYL- * TRANSFERASE CDP- CMP Ethanolamine Pi H2O O O O H2C O (CH2)2 R2 H2C O (CH2)2 R2 H2C O (CH2)2 R2

R3 C O C H R3 C O C H R3 C O C H H C O P CH CH NH CDP-ETHANOLAMINE: H C OH PHOSPHOHYDROLASE H C O P 2 2 2 2 ALKYLACYLGLYCEROL 2 2 PHOSPHOETHANOLAMINE 1-Alkyl-2-acylglycerol TRANSFERASE 3-phosphoethanolamine 1-Alkyl-2-acylglycerol 3-phosphate 1-Alkyl-2-acylglycerol CDP-choline NADPH, O2, DESATURASE CDP-CHOLINE: Cyt b ALKYLACYLGLYCEROL 5 PHOSPHOCHOLINE Alkyl, diacyl glycerols TRANSFERASE O CMP H2C O CH CH R2 O H C O (CH ) R 2 2 2 2 H O R COOH R3 C O C H 2 3 R3 C O C H H2C O (CH2)2 R2 H2C O P (CH2)2 NH2 H2C O P HO C H

PHOSPHOLIPASE A2 1-Alkenyl-2-acylglycerol Choline H2C O P 3-phosphoethanolamine plasmalogen 1-Alkyl-2-acylglycerol Choline 3-phosphocholine 1-Alkyl-2-lysoglycerol Acetyl-CoA 3-phosphocholine

ACETYLTRANSFERASE O H2C O (CH2)2 R2

H3C C O C H

H2C O P

Choline 1-Alkyl-2-acetylglycerol 3-phosphocholine PAF Figure 24–4. Biosynthesis of ether lipids, including plasmalogens, and platelet-activating factor (PAF). In the de novo pathway for PAF synthesis, acetyl-CoA is incorporated at stage *, avoiding the last two steps in the path- way shown here.

Phospholipases Allow Degradation solecithin) is attacked by , forming & Remodeling of Phosphoglycerols the corresponding glyceryl phosphoryl base, which in turn may be split by a liberating glycerol Although phospholipids are actively degraded, each 3-phosphate plus base. A1, A2, B, C, portion of the molecule turns over at a different rate— and D attack the bonds indicated in Figure 24–6. eg, the turnover time of the phosphate group is differ- A2 is found in pancreatic fluid and ent from that of the 1-acyl group. This is due to the snake venom as well as in many types of cells; phos- presence of enzymes that allow partial degradation fol- pholipase C is one of the major toxins secreted by bac- lowed by resynthesis (Figure 24–5). teria; and is known to be involved in catalyzes the hydrolysis of glycerophospholipids to form mammalian signal transduction. a free fatty acid and lysophospholipid, which in turn Lysolecithin (lysophosphatidylcholine) may be may be reacylated by acyl-CoA in the presence of an formed by an alternative route that involves lecithin: acyltransferase. Alternatively, lysophospholipid (eg, ly- acyltransferase (LCAT). This enzyme, ch24.qxd 2/13/2003 3:28 PM Page 201

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 201

O found in plasma, catalyzes the transfer of a fatty acid O H C O C R residue from the 2 position of lecithin to cholesterol to 2 1 form cholesteryl ester and lysolecithin and is considered R2 C O C H to be responsible for much of the cholesteryl ester in

H2C O P Choline plasma lipoproteins. Long-chain saturated fatty acids Phosphatidylcholine are found predominantly in the 1 position of phospho- lipids, whereas the polyunsaturated acids (eg, the pre- H2O cursors of prostaglandins) are incorporated more into

ACYLTRANSFERASE PHOSPHOLIPASE A the 2 position. The incorporation of fatty acids into 2 lecithin occurs by complete synthesis of the phospho-

R2 COOH lipid, by transacylation between cholesteryl ester and O lysolecithin, and by direct acylation of lysolecithin by H C O C R acyl-CoA. Thus, a continuous exchange of the fatty 2 1 acids is possible, particularly with regard to introducing HO C H essential fatty acids into phospholipid molecules. H2C O P Choline Acyl-CoA Lysophosphatidylcholine (lysolecithin) ALL SPHINGOLIPIDS ARE FORMED FROM CERAMIDE H2O

LYSOPHOSPHOLIPASE Ceramide is synthesized in the endoplasmic reticulum from the amino acid serine according to Figure 24–7. R1 COOH Ceramide is an important signaling molecule (second H C OH messenger) regulating pathways including apoptosis 2 (processes leading to cell death), cell senescence, and HO C H differentiation, and opposes some of the actions of di- H2C O P Choline acylglycerol. Glycerylphosphocholine Sphingomyelins (Figure 14–11) are phospholipids and are formed when ceramide reacts with phos- H2O phatidylcholine to form sphingomyelin plus diacylglyc- GLYCERYLPHOSPHO- erol (Figure 24–8A). This occurs mainly in the Golgi CHOLINE HYDROLASE apparatus and to a lesser extent in the plasma mem- brane.

H2C OH HO C H + Choline Glycosphingolipids Are a Combination of Ceramide With One or More H2C O P Sugar Residues sn-Glycerol 3-phosphate The simplest glycosphingolipids (cerebrosides) are Figure 24–5. Metabolism of phosphatidylcholine galactosylceramide (GalCer) and glucosylceramide (lecithin). (GlcCer). GalCer is a major lipid of myelin, whereas GlcCer is the major glycosphingolipid of extraneural tissues and a precursor of most of the more complex glycosphingolipids. Galactosylceramide (Figure 24–8B) O is formed in a reaction between ceramide and UDPGal (formed by epimerization from UDPGlc—Figure H2C O C R1 O 20–6). Sulfogalactosylceramide and other sulfolipids PHOSPHOLIPASE D R C O C H such as the sulfo(galacto)-glycerolipids and the 2 O sulfates are formed after further reactions in- ′ ′ H C O P O N-BASE volving 3 -phosphoadenosine-5 -phosphosulfate (PAPS; 2 “active sulfate”). Gangliosides are synthesized from – PHOSPHOLIPASE A2 O ceramide by the stepwise addition of activated sugars (eg, UDPGlc and UDPGal) and a sialic acid, usually N- acetylneuraminic acid (Figure 24–9). A large number Figure 24–6. Sites of the hydrolytic activity of phos- of gangliosides of increasing molecular weight may be pholipases on a phospholipid substrate. formed. Most of the enzymes transferring sugars from ch24.qxd 2/13/2003 3:28 PM Page 202

202 / CHAPTER 24

+ nucleotide sugars (glycosyl transferases) are found in O NH3 − the Golgi apparatus. CH3 (CH2)14 C S CoA OOCCH CH2 OH Glycosphingolipids are constituents of the outer Palmitoyl-CoA Serine leaflet of plasma membranes and are important in cell adhesion and cell recognition. Some are antigens, eg, ABO blood group substances. Certain gangliosides + Pyridoxal phosphate, Mn2 function as receptors for bacterial toxins (eg, for cholera toxin, which subsequently activates adenylyl cyclase). SERINE PALMITOYLTRANSFERASE CLINICAL ASPECTS CoA SH CO2 O Deficiency of Lung Surfactant Causes Respiratory Distress Syndrome CH3 (CH2)12 CH2 CH2 CCHCH2 OH + Lung surfactant is composed mainly of lipid with NH3 3-Ketosphinganine some proteins and carbohydrate and prevents the alve- NADPH + H+ oli from collapsing. Surfactant activity is largely attrib- uted to dipalmitoylphosphatidylcholine, which is 3-KETOSPHINGANINE REDUCTASE synthesized shortly before parturition in full-term in- NADP+ fants. Deficiency of lung surfactant in the lungs of many preterm newborns gives rise to respiratory dis- CH3(CH2)12 CH2 CH2 CH CHCH2 OH tress syndrome. Administration of either natural or ar- + OH NH3 tificial surfactant has been of therapeutic benefit. Dihydrosphingosine (sphinganine) Phospholipids & Sphingolipids R CO S CoA Are Involved in Multiple Sclerosis Acyl-CoA DIHYDROSPHINGOSINE N-ACYLTRANSFERASE and Lipidoses CoA SH Certain diseases are characterized by abnormal quanti-

CH3 (CH2)12 CH2 CH2 CH CHCH2 OH ties of these lipids in the tissues, often in the nervous OH NH CO R system. They may be classified into two groups: (1) true demyelinating diseases and (2) sphingolipidoses. Dihydroceramide In multiple sclerosis, which is a demyelinating dis- DIHYDROCERAMIDE ease, there is loss of both phospholipids (particularly 2H DESATURASE ethanolamine plasmalogen) and of sphingolipids from white matter. Thus, the lipid composition of white matter resembles that of gray matter. The cerebrospinal CH3 (CH2)12 CH CH CH CH CH2 OH fluid shows raised phospholipid levels. OH NH CO R The sphingolipidoses (lipid storage diseases) are a Ceramide group of inherited diseases that are often manifested in Figure 24–7. Biosynthesis of ceramide. childhood. These diseases are part of a larger group of lysosomal disorders and exhibit several constant fea- tures: (1) Complex lipids containing ceramide accumu- late in cells, particularly neurons, causing neurodegen-

A Ceramide Sphingomyelin

Phosphatidylcholine Diacylglycerol

Figure 24–8. Biosynthesis of sphingomyelin (A),

UDPGal UDP PAPS Sulfogalactosyl- galactosylceramide and its sulfo derivative (B). (PAPS, Galactosylceramide ceramide “active sulfate,” adenosine 3′-phosphate-5′-phospho- B Ceramide (cerebroside) (sulfatide) sulfate.) ch24.qxd 2/13/2003 3:28 PM Page 203

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 203

UDPGlc UDP UDPGal UDP CMP-NeuAc CMP

Glucosyl Ceramide ceramide Cer-Glc-Gal Cer-Glc-Gal (Cer-Glc) NeuAc

(GM3)

UDP-N-acetyl galactosamine

UDP UDPGal UDP

Higher gangliosides Cer-Glc-Gal-GalNAc-Gal Cer-Glc-Gal-GalNAc (disialo- and trisialo- gangliosides) NeuAc NeuAc

(GM1) (GM2)

Figure 24–9. Biosynthesis of gangliosides. (NeuAc, N-acetylneuraminic acid.)

eration and shortening the life span. (2) The rate of dase) in the treatment of Gaucher’s disease. A recent synthesis of the stored lipid is normal. (3) The enzy- promising approach is substrate reduction therapy to matic defect is in the lysosomal degradation pathway inhibit the synthesis of sphingolipids, and gene therapy of sphingolipids. (4) The extent to which the activity of for lysosomal disorders is currently under investigation. the affected enzyme is decreased is similar in all tissues. Some examples of the more important lipid storage dis- There is no effective treatment for many of the diseases, eases are shown in Table 24–1. though some success has been achieved with enzymes Multiple deficiency results in accumula- that have been chemically modified to ensure binding tion of sulfogalactosylceramide, steroid sulfates, and to receptors of target cells, eg, to macrophages in the proteoglycans owing to a combined deficiency of aryl- liver in order to deliver β-glucosidase (glucocerebrosi- A, B, and C and steroid sulfatase.

Table 24–1. Examples of sphingolipidoses.

Disease Enzyme Deficiency Lipid Accumulating1 Clinical Symptoms : Tay-Sachs disease Hexosaminidase A Cer—Glc—Gal(NeuAc)—: GalNAc Mental retardation, blindness, muscular weakness. GM2 Ganglioside α : Fabry’s disease -Galactosidase Cer—Glc—Gal—: Gal Skin rash, kidney failure (full symptoms only in Globotriaosylceramide males; X-linked recessive). : Metachromatic A Cer—Gal—: OSO3 Mental retardation and psychologic disturbances in leukodystrophy 3-Sulfogalactosylceramide adults; demyelination. β : Krabbe’s disease -Galactosidase Cer—: Gal Mental retardation; myelin almost absent. Galactosylceramide β : Gaucher’s disease -Glucosidase Cer—: Glc Enlarged liver and spleen, erosion of long bones, Glucosylceramide mental retardation in infants. : Niemann-Pick Sphingomyelinase Cer—: P—choline Enlarged liver and spleen, mental retardation; fatal in disease Sphingomyelin early life. : Farber’s disease Ceramidase Acyl—: Sphingosine Hoarseness, dermatitis, skeletal deformation, mental Ceramide retardation; fatal in early life. 1 : NeuAc, N-acetylneuraminic acid; Cer, ceramide; Glc, glucose; Gal, galactose. —: , site of deficient enzyme reaction. ch24.qxd 2/13/2003 3:28 PM Page 204

204 / CHAPTER 24

SUMMARY (demyelination), and sphingolipidoses (inability to break down sphingolipids in lysosomes due to inher- • Triacylglycerols are the major energy-storing lipids, ited defects in hydrolase enzymes). whereas phosphoglycerols, sphingomyelin, and gly- cosphingolipids are amphipathic and have structural functions in cell membranes as well as other special- ized roles. REFERENCES • Triacylglycerols and some phosphoglycerols are syn- Griese M: Pulmonary surfactant in health and human lung dis- thesized by progressive acylation of glycerol 3-phos- eases: state of the art. Eur Respir J 1999;13:1455. phate. The pathway bifurcates at phosphatidate, Merrill AH, Sweeley CC: Sphingolipids: metabolism and cell sig- forming inositol phospholipids and cardiolipin on naling. In: Biochemistry of Lipids, Lipoproteins and Mem- the one hand and triacylglycerol and choline and branes. Vance DE, Vance JE (editors). Elsevier, 1996. ethanolamine phospholipids on the other. Prescott SM et al: Platelet-activating factor and related lipid media- • Plasmalogens and platelet-activating factor (PAF) are tors. Annu Rev Biochem 2000;69:419. ether phospholipids formed from dihydroxyacetone Ruvolo PP: Ceramide regulates cellular homeostasis via diverse phosphate. stress signaling pathways. Leukemia 2001;15:1153. Schuette CG et al: The glycosphingolipidoses—from disease to • Sphingolipids are formed from ceramide (N-acyl- basic principles of metabolism. Biol Chem 1999;380:759. sphingosine). Sphingomyelin is present in mem- Scriver CR et al (editors): The Metabolic and Molecular Bases of In- branes of organelles involved in secretory processes herited Disease, 8th ed. McGraw-Hill, 2001. (eg, Golgi apparatus). The simplest glycosphin- Tijburg LBM, Geelen MJH, van Golde LMG: Regulation of the golipids are a combination of ceramide plus a sugar biosynthesis of triacylglycerol, phosphatidylcholine and phos- residue (eg, GalCer in myelin). Gangliosides are phatidylethanolamine in the liver. Biochim Biophys Acta more complex glycosphingolipids containing more 1989;1004:1. sugar residues plus sialic acid. They are present in the Vance DE: Glycerolipid biosynthesis in eukaryotes. In: Biochem- outer layer of the plasma membrane, where they con- istry of Lipids, Lipoproteins and Membranes. Vance DE, Vance tribute to the glycocalyx and are important as anti- JE (editors). Elsevier, 1996. van Echten G, Sandhoff K: Ganglioside metabolism. Enzymology, gens and cell receptors. topology, and regulation. J Biol Chem 1993;268:5341. • Phospholipids and sphingolipids are involved in sev- Waite M: Phospholipases. In: Biochemistry of Lipids, Lipoproteins eral disease processes, including respiratory distress and Membranes. Vance DE, Vance JE (editors). Elsevier, syndrome (lack of lung surfactant), multiple sclerosis 1996.