Harper's Biochemistry Chapter 24 - Metabolism of Acylglycerols & Sphingolipids PDF

C H A P T E R Metabolism of Acylglycerols & Sphingolipids Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 24 O B J E C TI V E S Explain that the catabol...

C H A P T E R Metabolism of Acylglycerols & Sphingolipids Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 24 O B J E C TI V E S Explain that the catabolism of triacylglycerols involves hydrolysis to free fatty acids and glycerol and indicate the fate of these metabolites. After studying this chapter, Indicate that glycerol-3-phosphate is the substrate for the formation of you should be able to: both triacylglycerols and phosphoglycerols and that a branch point at phosphatidate leads to the synthesis of inositol phospholipids and cardiolipin or/and triacylglycerols and other phospholipids. Explain that plasmalogens and platelet-activating factor (PAF) are formed by a complex pathway starting from dihydroxyacetone phosphate. Illustrate the role of various phospholipases in the degradation and remodeling of phospholipids. Explain that ceramide is the precursor from which all sphingolipids are formed. Indicate how sphingomyelin and glycosphingolipids are produced by the reaction of ceramide with phosphatidylcholine or sugar residue(s), respectively. Identify examples of disease processes caused by defects in phospholipid or sphingolipid synthesis or breakdown. BIOMEDICAL IMPORTANCE blood group substances. A dozen or so glycolipid storage dis- eases have been described (eg, Gaucher disease and Tay-Sachs Acylglycerols constitute the majority of lipids in the body. Tri- disease), each due to a genetic defect in the pathway for glyco- acylglycerols are the major lipids in fat deposits and in food, lipid degradation in the lysosomes. and their roles in lipid transport and storage and in various diseases such as obesity, diabetes, and hyperlipoproteinemia will be described in subsequent chapters. The amphipathic HYDROLYSIS INITIATES nature of phospholipids and sphingolipids makes them ideally CATABOLISM OF suitable as the main lipid component of cell membranes. Phospholipids also take part in the metabolism of many TRIACYLGLYCEROLS other lipids. Some phospholipids have specialized functions; Triacylglycerols must be hydrolyzed by a lipase to their con- for example, dipalmitoyl lecithin is a major component of lung stituent fatty acids and glycerol before further catabolism surfactant, which is lacking in respiratory distress syndrome can proceed. Much of this hydrolysis (lipolysis) occurs in of the newborn. Inositol phospholipids in the cell membrane adipose tissue with release of free fatty acids into the plasma, act as precursors of hormone second messengers, and platelet- where they are found combined with serum albumin (see activating factor (PAF), an alkylphospholipid, functions in Figure 25–7). This is followed by free fatty acid uptake into the mediation of inflammation. Glycosphingolipids, which tissues (including liver, heart, kidney, muscle, lung, testis, contain sphingosine and sugar residues as well as a fatty acid, and adipose tissue, but not readily by brain), where they are are found in the outer leaflet of the plasma membrane with oxidized to obtain energy or reesterified. The utilization of their oligosaccharide chains facing outward. They form part glycerol depends on whether such tissues have the enzyme of the glycocalyx of the cell surface and are important (1) in glycerol kinase, which is found in significant amounts in cell adhesion and cell recognition, (2) as receptors for bacte- liver, kidney, intestine, brown adipose tissue, and the lactat- rial toxins (eg, the toxin that causes cholera), and (3) as ABO ing mammary gland. 239 240 SECTION V Metabolism of Lipids TRIACYLGLYCEROLS & phosphatidate (see Figure 24–2). In the triacylglycerol branch of the pathway, phosphatidate is converted by phosphatidate PHOSPHOGLYCEROLS ARE phosphohydrolase (also called phosphatidate phosphatase FORMED BY ACYLATION OF [PAP]) to 1,2-diacylglycerol which is then converted to triacyl- TRIOSE PHOSPHATES glycerol by diacylglycerol acyltransferase (DGAT). Lipins, a family of three proteins, have phosphatidate phosphohydrolase The major pathways of triacylglycerol and phosphoglycerol activity and they also act as transcription factors which regulate biosynthesis are outlined in Figure 24–1. Important substances the expression of genes involved in lipid metabolism. DGAT such as triacylglycerols, phosphatidylcholine, phosphatidyletha- catalyzes the only step specific for triacylglycerol synthesis and nolamine, phosphatidylinositol, and cardiolipin, a constituent is thought to be rate limiting in most circumstances. In intestinal of mitochondrial membranes, are formed from glycerol- mucosa, monoacylglycerol acyltransferase converts monoacyl- 3-phosphate. Significant branch points in the pathway occur at glycerol to 1,2-diacylglycerol in the monoacylglycerol pathway. the phosphatidate and diacylglycerol steps. Dihydroxyacetone Most of the activity of these enzymes resides in the endoplasmic phosphate is the precursor for phosphoglycerols containing an reticulum, but some is found in mitochondria. Although phos- ether link (—C—O—C—), the best known of which are plas- phatidate phosphohydrolase protein is found mainly in the cyto- malogens and PAF. Both glycerol-3-phosphate and dihydroxy- sol, the active form of the enzyme is membrane bound. acetone phosphate are intermediates in glycolysis, making a very important connection between carbohydrate and lipid metabo- lism (see Chapter 14). Biosynthesis of Phospholipids Both the glycerol and fatty acid components must be acti- The biosynthesis of phosphatidylcholine and phosphatidyl- vated by ATP before they can be incorporated into acylglycerols. ethanolamine also involves the conversion of phosphatidate Glycerol kinase catalyzes the activation of glycerol to sn- to 1,2-diacylglycerol (see Figure 24–2). Before the next step, glycerol-3-phosphate. If the activity of this enzyme is absent or however, choline or ethanolamine must first be activated by low, as in muscle or adipose tissue, most of the glycerol- phosphorylation by ATP and then linked to CDP. The resulting 3-phosphate is formed from dihydroxyacetone phosphate by CDP-choline or CDP-ethanolamine reacts with 1,2-diacylglycerol glycerol-3-phosphate dehydrogenase (Figure 24–2). to form either phosphatidylcholine or phosphatidylethanolamine, respectively (see Figure 24–2, lower left). In the case of phospha- tidylinositol formation, it is phosphatidate that is linked to CDP, Phosphatidate Is the Common forming CDP-diacylglycerol, which is then linked to inositol by Precursor in the Biosynthesis phosphatidylinositol synthase. The second messenger, phos- of Triacylglycerols, Many phatidylinositol 4,5 bisphosphate (PIP2) (see Chapter 21), which regulates essential cell functions including signal trans- Phosphoglycerols, & Cardiolipin duction and vesicle trafficking, is synthesized by two further Biosynthesis of Triacylglycerols kinase catalyzed steps (see Figure 24–2, lower right). Phosphati- Acyl-CoA, formed by the activation of fatty acids by acyl-CoA dylserine is formed from phosphatidylethanolamine directly by synthetase(see Chapter 22), combines with glycerol-3-phosphate reaction with serine. Phosphatidylserine may reform phospha- in two successive reactions catalyzed by glycerol-3-phosphate tidylethanolamine by decarboxylation (see Figure 24–2, bottom acyltransferase and 1-acylglycerol-3-phosphate acyltransfer- left). An alternative pathway in liver enables phosphatidyletha- ase, resulting in the formation of 1,2-diacylglycerol phosphate or nolamine to give rise directly to phosphatidylcholine by pro- gressive methylation of the ethanolamine residue. Despite these endogenous sources of choline, it is considered to be an essential nutrient for humans and many other mammalian species. Glycerol-3-phosphate Dihydroxyacetone phosphate The regulation of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine biosynthesis is driven by the availability of free fatty acids. Those not required for oxida- tion are preferentially converted to phospholipids, and when Phosphatidate Plasmalogens PAF this requirement is satisfied, they are used for triacylglycerol synthesis. Cardiolipin (diphosphatidylglycerol; see Figure 21–9) is Diacylglycerol Cardiolipin Phosphatidylinositol a phospholipid present in mitochondria. It is formed from phosphatidylglycerol, which in turn is synthesized from CDP- diacylglycerol (see Figure 24–2) and glycerol-3-phosphate. Phosphatidylcholine Triacylglycerol Phosphatidylinositol Cardiolipin, found in the inner membrane of mitochondria, Phosphatidylethanolamine 4,5-bisphosphate has a key role in mitochondrial structure and function, and FIGURE 24–1 Overview of acylglycerol biosynthesis. is also thought to be involved in programmed cell death (PAF, platelet-activating factor.) (apoptosis).  CHAPTER 24 Metabolism of Acylglycerols & Sphingolipids 241 ATP ADP NAD+ NADH + H+ H 2C OH H 2C OH H 2C OH HO C H HO C H C O 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 Choline phosphohydrolase synthase kinase P1 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 CMP CoA 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 H 2C O P O H 2C O C R3 O H 2C O P O H 2C O P Inositol P Triacyglycerol Choline Inositol Phosphatidylinositol 4-phosphate Phosphatidylcholine Phosphatidylinositol ATP Phosphatidylethanolamine N-methyltransferase (–CH3)3 Kinase Phosphatidylethanolamine Serine CO2 ADP O H 2C O C R1 Phosphatidylserine Ethanolamine R2 C O C H O H 2C O P Inositol P P Phosphatidylinositol 4,5-bisphosphate FIGURE 24–2 Biosynthesis of triacylglycerol and phospholipids. 1 , monoacylglycerol pathway; 2 , glycerol phosphate pathway. Phosphatidylethanolamine may be formed from ethanolamine by a pathway similar to that shown for the formation of phosphatidylcholine from choline. 242 SECTION V Metabolism of Lipids Biosynthesis of Glycerol Ether Phospholipids 3-phosphoethanolamine derivative (see Figure 24–3), while In glycerol ether phospholipids, one or more of the glycerol PAF (1-alkyl-2-acetyl-sn-glycerol-3-phosphocholine) is syn- carbons is attached to a hydrocarbon chain by an ether linkage thesized by acetylation of the corresponding 3-phosphocholine rather than an ester bond. Plasmalogens and PAF are impor- derivative. Production of PAF occurs in many cell types, but tant examples of this type of lipid. The biosynthetic pathway is particularly leukocytes and endothelial cells. It was recog- located in peroxisomes. The precursor dihydroxyacetone phos- nized initially for its platelet aggregating properties, but is now phate combines with acyl-CoA to give 1-acyldihydroxyacetone known to mediate inflammation, and can contribute to aller- phosphate, and the ether link is formed in the next reaction, gic reactions and shock. producing 1-alkyldihydroxyacetone phosphate, which is then converted to 1-alkylglycerol 3-phosphate (Figure 24–3). After further acylation in the 2 position, the resulting 1-alkyl- Phospholipases Allow Degradation & 2-acylglycerol 3-phosphate (analogous to phosphatidate in Remodeling of Phosphoglycerols Figure 24–2) is hydrolyzed to give 1-alkyl-2-acylglycerol. As in Although phospholipids are actively degraded, each por- the pathway for phospholipid biosynthesis (see Figure 24–2), tion of the molecule turns over at a different rate—for exam- the next steps in the formation of plasmalogens and PAF ple, the turnover time of the phosphate group is different require CDP-ethanolamine and CDP-choline, respectively. from that of the 1-acyl group. This is due to the presence of Plasmalogens, which comprise much of the phospholipid in enzymes that allow partial degradation followed by resynthe- mitochondria, are produced by desaturation of the resulting sis (Figure 24–4). Phospholipase A2 catalyzes the hydrolysis of 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 2C O P Acyl- H 2C O P Synthase H 2C O P Reductase H 2C O P transferase HOOC R1 Dihydroxyacetone 1-Acyldihydroxyacetone 1-Alkyldihydroxyacetone 1-Alkylglycerol 3-phosphate phosphate phosphate phosphate Acyl-CoA Acyl- * transferase CDP- CMP Ethanolamine Pi H 2O O H2C O (CH2)2 R2 O H2C O (CH2)2 R2 O H2C O (CH2)2 R2 R3 C O C H R3 C O C H R3 C O C H (CH2)2 CDP-ethanolamine: Phosphohydrolase H 2C O P NH2 H 2C OH H 2C O P alkylacylglycerol 1-Alkyl-2-acylglycerol phosphoethanolamine 3-phosphoethanolamine transferase 1-Alkyl-2-acylglycerol 3-phosphate 1-Alkyl-2-acylglycerol CDP-choline NADPH, O2, CDP-choline: Desaturase Cyt b5 alkylacylglycerol Alkyl, diacylglycerols phosphocholine transferase O CMP H2C O CH CH R2 O H2C O (CH2)2 R2 R3 C O C H H 2O R3 COOH R3 C O C H H2C O (CH2)2 R2 H 2C O P (CH2)2 NH2 H 2C O P HO C H Phospholipase A2 H2C O P 1-Alkenyl-2-acylglycerol Choline 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 H 3C C O C H H 2C O P Choline 1-Alkyl-2-acetylglycerol 3-phosphocholine PAF FIGURE 24–3 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 pathway shown here.  CHAPTER 24 Metabolism of Acylglycerols & Sphingolipids 243 O Phospholipase B Phospholipase A1 O H2C O C R1 O R2 C O C H H2C O C R1 O H2 C O P Choline Phospholipase D R2 C O C H Phosphatidylcholine O H2O H2 C O P O N-base Acyltransferase Phospholipase A2 Phospholipase A2 – O R2 COOH Phospholipase C O H2C O C R1 FIGURE 24–5 Sites of the hydrolytic activity of phospholipases on a phospholipid substrate. HO C H H2C O P Choline Acyl-CoA Lysophosphatidylcholine (lysolecithin) Long-chain saturated fatty acids are found predomi- H2O nantly in the 1 position of phospholipids, whereas the poly- Lysophospholipase unsaturated fatty acids (eg, the precursors of prostaglandins) are incorporated more frequently into the 2 position. The R1 COOH incorporation of fatty acids into phosphatidylcholine occurs H2C OH in three ways; by complete synthesis of the phospholipid HO C H (see Figure 24–4); by transacylation between cholesteryl H2 C O P Choline ester and lysophosphatidylcholine; and by direct acylation Glycerylphosphocholine of lysophosphatidylcholine by acyl-CoA. Thus, a continuous exchange of the fatty acids is possible, particularly with regard H2O to introducing essential fatty acids (see Chapter 21) into phospho- Glycerylphospho- choline hydrolase lipid molecules. H2C OH HO C H + Choline ALL SPHINGOLIPIDS ARE H2 C O P FORMED FROM CERAMIDE sn-Glycerol 3-phosphate Ceramide (see Chapter 21) is synthesized in the endoplasmic reticulum from the amino acid serine as shown in Figure 24–6. FIGURE 24–4 Metabolism of phosphatidylcholine (lecithin). Ceramide is an important signaling molecule (second mes- senger) regulating pathways including programmed cell death glycerophospholipids to form a free fatty acid and lysophospho- (apoptosis), the cell cycle, and cell differentiation and lipid, which in turn may be reacylated by acyl-CoA in the pres- senescence. ence of an acyltransferase. Alternatively, lysophospholipid (eg, Sphingomyelins (see Figure 21–10) are phospholipids and lysolecithin) is attacked by lysophospholipase, forming the are formed when ceramide reacts with phosphatidylcholine to corresponding glyceryl phosphoryl base (choline is shown as form sphingomyelin plus diacylglycerol (Figure 24–7A). This an example base in Figure 24–4), which may then be split by a occurs mainly in the Golgi apparatus and to a lesser extent in hydrolase liberating glycerol-3-phosphate plus base. Phos- the plasma membrane. pholipases A1, A 2, B, C, and D attack the bonds indicated in Figure 24–5. Phospholipase A2 is found in pancreatic fluid and snake venom as well as in many types of cells; phospho- Glycosphingolipids Are a Combination lipase C is one of the major toxins secreted by bacteria; and phospholipase D is known to be involved in mammalian sig- of Ceramide With One or More Sugar nal transduction. Residues Lysophosphatidylcholine, also called lysolecithin, may The simplest glycosphingolipids (cerebrosides) are galactosyl- be formed by an alternative route that involves lecithin ceramide (GalCer) (see Figure 21–14) and glucosylceramide (phosphatidylcholine): cholesterol acyltransferase (LCAT). (GlcCer). GalCer is a major lipid of myelin, whereas GlcCer is This enzyme, found in plasma, catalyzes the transfer of a fatty the major glycosphingolipid of extraneural tissues and a pre- acid residue from the 2 position of lecithin to cholesterol to cursor of most of the more complex glycosphingolipids. GalCer form cholesteryl ester and lysolecithin, and is considered to be (Figure 24–7B) is formed in a reaction between ceramide and responsible for much of the cholesteryl ester in plasma lipo- uridine diphosphate galactose (UDPGal) (formed by epimer- proteins (see Chapter 25). ization from UDPGlc; see Figure 20–6). 244 SECTION V Metabolism of Lipids O + NH3 A Ceramide Sphingomyelin – CH3 (CH2)14 C S CoA OOC CH CH2 OH Phosphatidylcholine Diacylglycerol Palmitoyl-CoA Serine Pyridoxal phosphate, Mn2+ UDPGal UDP PAPS Sulfogalactosyl- Galactosylceramide ceramide Serine B Ceramide (cerebroside) (sulfatide) palmitoyltransferase CoA SH CO2 FIGURE 24–7 Biosynthesis of (A) sphingomyelin, (B) galacto- sylceramide and its sulfo derivative. (PAPS, “active sulfate,” adenosine O 3′-phosphate-5′-phosphosulfate.) CH3 (CH2)12 CH2 CH2 C CH CH2 OH + NH3 3-Ketosphinganine NADPH + H+ and are synthesized from ceramide by the stepwise addition 3-Ketosphinganine of activated sugars (eg, UDPGlc and UDPGal) and a sialic reductase acid, usually N-acetylneuraminic acid (Figure 24–8). A large NADP+ number of gangliosides of increasing molecular weight may be CH3(CH2)12 CH2 CH2 CH CH CH2 OH formed. Most of the enzymes transferring sugars from nucleo- OH NH3 + tide sugars (glycosyl transferases) are found in the Golgi appa- Dihydrosphingosine (sphinganine) ratus. Certain gangliosides function as receptors for bacterial toxins (eg, for cholera toxin, which subsequently activates Acyl-CoA Dihydrosphingosine adenylyl cyclase). N-acyltransferase Glycosphingolipids are constituents of the outer leaflet of CoA plasma membranes and are important in cell adhesion, cell CH3 (CH2)12 CH2 CH2 CH CH CH2 OH recognition, and signal transduction. Some are antigens, for example, ABO blood group substances. OH NH CO R Dihydroceramide Dihydroceramide desaturase 2H CLINICAL ASPECTS CH3 (CH2)12 CH CH CH CH CH2 OH Deficiency of Lung Surfactant Causes OH NH CO R Respiratory Distress Syndrome Ceramide Lung surfactant is composed mainly of lipid with some pro- FIGURE 24–6 Biosynthesis of ceramide. teins and carbohydrate and prevents the alveoli from collapsing. The phospholipid dipalmitoyl-phosphatidylcholine decreases Sulfogalactosylceramide (sulfatide), a component of surface tension at the air-liquid interface and thus greatly reduces the myelin sheath, is formed by a further reaction involving the work of breathing, but other surfactant lipid and protein com- 3′-phosphoadenosine-5′-phosphosulfate (PAPS; “active sulfate”). ponents are also important in surfactant function. Deficiency Gangliosides are found in cell membranes (see Chapter 40), of lung surfactant in the lungs of many preterm newborns gives UDPGlc UDP UDPGal UDP CMP-NeuAc CMP Glucosyl Ceramide ceramide Cer-Glc-Gal Cer-Glc-Gal (Cer-Glc) NeuAc UDP-N-acetyl galactosamine UDP UDPGal UDP Higher gangliosides Cer-Glc-Gal-GalNAc-Gal Cer-Glc-Gal-GalNAc (disialo- and trisialo- gangliosides) NeuAc NeuAc FIGURE 24–8 Biosynthesis of gangliosides. (NeuAc, N-acetylneuraminic acid.)  CHAPTER 24 Metabolism of Acylglycerols & Sphingolipids 245 TABLE 24–1 Examples of Sphingolipidoses Disease Enzyme Deficiency Lipid Accumulating Clinical Symptoms Tay-Sachs disease Hexosaminidase A, S Cer—Glc—Gal(NeuAc) GalNAc GM2 Mental retardation, blindness, muscular weakness Ganglioside Fabry disease α-Galactosidase Cer—Glc—Gal— Gal Skin rash, kidney failure (full symptoms only in males; Globotriaosylceramide X-linked recessive) Metachromatic Arylsulfatase A Cer—Gal— OSO3 Mental retardation and psychologic disturbances in leukodystrophy 3-Sulfogalactosylceramide adults; demyelination Krabbe disease β-Galactosidase Cer— Gal Galactosylceramide Mental retardation; myelin almost absent Gaucher disease β-Glucosidase Cer— Glc Glucosylceramide Enlarged liver and spleen, erosion of long bones, mental retardation in infants Niemann-Pick Sphingomyelinase Cer— P—choline Sphingomyelin Enlarged liver and spleen, mental retardation; fatal in disease types A, B early life Farber disease Ceramidase Acyl— Sphingosine Ceramide Hoarseness, dermatitis, skeletal deformation, mental retardation; fatal in early life Abbreviations: Cer, ceramide; Gal, galactose; Glc, glucose; NeuAc, N-acetylneuraminic acid; , site of deficient enzyme reaction. rise to infant respiratory distress syndrome (IRDS). Adminis- Gene therapy for lysosomal disorders is also currently under tration of either natural or artificial surfactant is of therapeutic investigation. Some examples of the more important lipid stor- benefit. age diseases are shown in Table 24–1. Multiple sulfatase deficiency results in accumulation of sulfogalactosylceramide, steroid sulfates, and proteoglycans Phospholipids & Sphingolipids Are owing to a combined deficiency of arylsulfatases A, B, and C Involved in Multiple Sclerosis & and steroid sulfatase. Symptoms include abnormalities in neu- rologic and metabolic functions, as well as in hearing, sight, Lipidoses and bone. Metachromatic leukodystrophy is characterized by Certain diseases are characterized by abnormal quantities of a build-up of sulfatides in tissues caused by a defect in arylsul- these lipids in the tissues, often in the nervous system. They fatase A, and leads to irreversible damage to the myelin sheath. may be classified into two groups: (1) true demyelinating dis- eases and (2) sphingolipidoses. In multiple sclerosis, which is a demyelinating disease, SUMMARY there is loss of both phospholipids (particularly ethanolamine Triacylglycerols and some phosphoglycerols are synthesized plasmalogen) and of sphingolipids from white matter. Thus, by progressive acylation of glycerol-3-phosphate. The pathway the lipid composition of white matter resembles that of gray bifurcates at phosphatidate, forming inositol phospholipids and matter. The cerebrospinal fluid shows raised phospholipid cardiolipin on the one hand and triacylglycerol and choline and levels. ethanolamine phospholipids on the other. The sphingolipidoses (lipid storage diseases) are a group Plasmalogens and PAF are ether phospholipids formed from of inherited diseases that are caused by a genetic defect in the dihydroxyacetone phosphate. catabolism of lipids containing sphingosine. They are part of a Sphingolipids are formed from ceramide (N-acylsphingosine). larger group of lysosomal disorders and exhibit several constant Sphingomyelin is present in membranes of organelles involved features: (1) complex lipids containing ceramide accumulate in secretory processes (eg, Golgi apparatus). The simplest in cells, particularly neurons, causing neurodegeneration and glycosphingolipids are a combination of ceramide plus a sugar residue (eg, GalCer in myelin). Gangliosides are more complex shortening the life span. (2) The rate of synthesis of the stored glycosphingolipids containing more sugar residues plus lipid is normal. (3) The enzymatic defect is in the degradation sialic acid. They are present in the outer layer of the plasma pathway of sphingolipids in lysosomes. (4) The extent to which membrane, where they contribute to the glycocalyx and are the activity of the affected enzyme is decreased is similar in all important as antigens and cell receptors. tissues. There is no effective treatment for many of the dis- Phospholipids and sphingolipids are involved in several eases, although some success has been achieved with enzyme disease processes, including infant respiratory distress replacement therapy and bone marrow transplantation in syndrome (lack of lung surfactant), multiple sclerosis the treatment of Gaucher and Fabry diseases. Other promising (demyelination), and sphingolipidoses (inability to break approaches are substrate deprivation therapy to inhibit the down sphingolipids in lysosomes due to inherited defects in synthesis of sphingolipids and chemical chaperone therapy. hydrolase enzymes). 246 SECTION V Metabolism of Lipids Ridgway ND: Phospholipid synthesis in mammalian cells. In REFERENCES Biochemistry of Lipids, Lipoproteins and Membranes, 6th ed. Eljamil AS: Lipid Biochemistry: For Medical Sciences. iUniverse, Academic Press, 2015:210-236. 2015. Futerman AH: Sphingolipids. In Biochemistry of Lipids, Lipoproteins and Membranes, 6th ed. Ridgway N, McLeod R (editors). Academic Press, 2015:297-327.