C H A P T E R

Metabolism of Acylglycerols
& Sphingolipids
Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc
OBJ E C TI VE S
After studying this chapter,
you should be able to:
24
■ Explain that the catabolism of triacylglycerols involves hydrolysis to free fatty
acids and glycerol and indicate the fate of these metabolites.
■ Indicate that glycerol-3-phosphate is the substrate for the formation of
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-

Acylglycerols constitute the majority of lipids in the body. Tri-
acylglycerols are the major lipids in fat deposits and in food,
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
nature of phospholipids and sphingolipids makes them ideally
suitable as the main lipid component of cell membranes.
Phospholipids also take part in the metabolism of many
other lipids. Some phospholipids have specialized functions;
for example, dipalmitoyl lecithin is a major component of lung
surfactant, which is lacking in respiratory distress syndrome
of the newborn. Inositol phospholipids in the cell membrane
act as precursors of hormone second messengers, and platelet-
activating factor (PAF), an alkylphospholipid, functions in
the mediation of inflammation. Glycosphingolipids, which
contain sphingosine and sugar residues as well as a fatty acid,
are found in the outer leaflet of the plasma membrane with
their oligosaccharide chains facing outward. They form part
of the glycocalyx of the cell surface and are important (1) in
cell adhesion and cell recognition, (2) as receptors for bacte-
rial toxins (eg, the toxin that causes cholera), and (3) as ABO
eases have been described (eg, Gaucher disease and Tay-Sachs
disease), each due to a genetic defect in the pathway for glyco-
lipid degradation in the lysosomes.
HYDROLYSIS INITIATES
CATABOLISM OF
TRIACYLGLYCEROLS
Triacylglycerols must be hydrolyzed by a lipase to their con-
stituent fatty acids and glycerol before further catabolism
can proceed. Much of this hydrolysis (lipolysis) occurs in
adipose tissue with release of free fatty acids into the plasma,
where they are found combined with serum albumin (see
Figure 25–7). This is followed by free fatty acid uptake into
tissues (including liver, heart, kidney, muscle, lung, testis,
and adipose tissue, but not readily by brain), where they are
oxidized to obtain energy or reesterified. The utilization of
glycerol depends on whether such tissues have the enzyme
glycerol kinase, which is found in significant amounts in
liver, kidney, intestine, brown adipose tissue, and the lactat-
ing mammary gland.

239
240 SECTION V Metabolism of Lipids
TRIACYLGLYCEROLS &
PHOSPHOGLYCEROLS ARE
FORMED BY ACYLATION OF
TRIOSE PHOSPHATES
The major pathways of triacylglycerol and phosphoglycerol
biosynthesis are outlined in Figure 24–1. Important substances
such as triacylglycerols, phosphatidylcholine, phosphatidyletha-
nolamine, phosphatidylinositol, and cardiolipin, a constituent
of mitochondrial membranes, are formed from glycerol-
3-phosphate. Significant branch points in the pathway occur at
the phosphatidate and diacylglycerol steps. Dihydroxyacetone
phosphate is the precursor for phosphoglycerols containing an
ether link (—C—O—C—), the best known of which are plas-
malogens and PAF. Both glycerol-3-phosphate and dihydroxy-
acetone phosphate are intermediates in glycolysis, making a very
important connection between carbohydrate and lipid metabo-
lism (see Chapter 14).
Both the glycerol and fatty acid components must be acti-
vated by ATP before they can be incorporated into acylglycerols.
Glycerol kinase catalyzes the activation of glycerol to 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 dihydroxyacetone phosphate by
glycerol-3-phosphate dehydrogenase (Figure 24–2).
Phosphatidate Is the Common
Precursor in the Biosynthesis
of Triacylglycerols, Many
Phosphoglycerols, & Cardiolipin
Biosynthesis of Triacylglycerols
Acyl-CoA, formed by the activation of fatty acids by acyl-CoA
synthetase(see Chapter 22), combines with glycerol-3-phosphate
in two successive reactions catalyzed by glycerol-3-phosphate
acyltransferase and 1-acylglycerol-3-phosphate acyltransfer-
ase, resulting in the formation of 1,2-diacylglycerol phosphate or
Glycerol-3-phosphate Dihydroxyacetone phosphate
Phosphatidate Plasmalogens
Diacylglycerol Cardiolipin Phosphatidylinositol
Phosphatidylcholine Triacylglycerol Phosphatidylinositol
Phosphatidylethanolamine 4,5-bisphosphate
FIGURE 24–1 Overview of acylglycerol biosynthesis.
(PAF, platelet-activating factor.)
phosphatidate (see Figure 24–2). In the triacylglycerol branch
of the pathway, phosphatidate is converted by phosphatidate
phosphohydrolase (also called phosphatidate phosphatase
[PAP]) to 1,2-diacylglycerol which is then converted to triacyl-
glycerol by diacylglycerol acyltransferase (DGAT). Lipins, a
family of three proteins, have phosphatidate phosphohydrolase
activity and they also act as transcription factors which regulate
the expression of genes involved in lipid metabolism. DGAT
catalyzes the only step specific for triacylglycerol synthesis and
is thought to be rate limiting in most circumstances. In intestinal
mucosa, monoacylglycerol acyltransferase converts monoacyl-
glycerol to 1,2-diacylglycerol in the monoacylglycerol pathway.
Most of the activity of these enzymes resides in the endoplasmic
reticulum, but some is found in mitochondria. Although phos-
phatidate phosphohydrolase protein is found mainly in the cyto-
sol, the active form of the enzyme is membrane bound.
Biosynthesis of Phospholipids
The biosynthesis of phosphatidylcholine and phosphatidyl-
ethanolamine also involves the conversion of phosphatidate
to 1,2-diacylglycerol (see Figure 24–2). Before the next step,
however, choline or ethanolamine must first be activated by
phosphorylation by ATP and then linked to CDP. The resulting
CDP-choline or CDP-ethanolamine reacts with 1,2-diacylglycerol
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,
forming CDP-diacylglycerol, which is then linked to inositol by
phosphatidylinositol synthase. The second messenger, phos-
phatidylinositol 4,5 bisphosphate (PIP2) (see Chapter 21),
which regulates essential cell functions including signal trans-
duction and vesicle trafficking, is synthesized by two further
kinase catalyzed steps (see Figure 24–2, lower right). Phosphati-
dylserine is formed from phosphatidylethanolamine directly by
reaction with serine. Phosphatidylserine may reform phospha-
tidylethanolamine by decarboxylation (see Figure 24–2, bottom
left). An alternative pathway in liver enables phosphatidyletha-
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.
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
PAF this requirement is satisfied, they are used for triacylglycerol
synthesis.
Cardiolipin (diphosphatidylglycerol; see Figure 21–9) is
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.
Cardiolipin, found in the inner membrane of mitochondria,
has a key role in mitochondrial structure and function, and
is also thought to be involved in programmed cell death
(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
H2 C O P
sn-Glycerol 3-phosphate
FIGURE 24–4 Metabolism of phosphatidylcholine (lecithin).
glycerophospholipids to form a free fatty acid and lysophospho-
lipid, which in turn may be reacylated by acyl-CoA in the pres-
ence of an acyltransferase. Alternatively, lysophospholipid (eg,
lysolecithin) is attacked by lysophospholipase, forming the
corresponding glyceryl phosphoryl base (choline is shown as
an example base in Figure 24–4), which may then be split by a
hydrolase liberating glycerol-3-phosphate plus base. Phos-
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-
lipase C is one of the major toxins secreted by bacteria; and
phospholipase D is known to be involved in mammalian sig-
nal transduction.
Lysophosphatidylcholine, also called lysolecithin, may
be formed by an alternative route that involves lecithin
(phosphatidylcholine): cholesterol acyltransferase (LCAT).
This enzyme, found in plasma, catalyzes the transfer of a fatty
acid residue from the 2 position of lecithin to cholesterol to
form cholesteryl ester and lysolecithin, and is considered to be
responsible for much of the cholesteryl ester in plasma lipo-
proteins (see Chapter 25).
ALL SPHINGOLIPIDS ARE
FORMED FROM CERAMIDE
Ceramide (see Chapter 21) is synthesized in the endoplasmic
reticulum from the amino acid serine as shown in Figure 24–6.
Ceramide is an important signaling molecule (second mes-
senger) regulating pathways including programmed cell death
(apoptosis), the cell cycle, and cell differentiation and
senescence.
Sphingomyelins (see Figure 21–10) are phospholipids and
are formed when ceramide reacts with phosphatidylcholine to
form sphingomyelin plus diacylglycerol (Figure 24–7A). This
occurs mainly in the Golgi apparatus and to a lesser extent in
the plasma membrane.
Glycosphingolipids Are a Combination
of Ceramide With One or More Sugar
Residues
The simplest glycosphingolipids (cerebrosides) are galactosyl-
ceramide (GalCer) (see Figure 21–14) and glucosylceramide
(GlcCer). GalCer is a major lipid of myelin, whereas GlcCer is
the major glycosphingolipid of extraneural tissues and a pre-
cursor of most of the more complex glycosphingolipids. GalCer
(Figure 24–7B) is formed in a reaction between ceramide and
uridine diphosphate galactose (UDPGal) (formed by epimer-
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-
tration of either natural or artificial surfactant is of therapeutic
benefit.
Phospholipids & Sphingolipids Are
Involved in Multiple Sclerosis &
Lipidoses
Certain diseases are characterized by abnormal quantities of
these lipids in the tissues, often in the nervous system. They
may be classified into two groups: (1) true demyelinating dis-
eases and (2) sphingolipidoses.
In multiple sclerosis, which is a demyelinating disease,
there is loss of both phospholipids (particularly ethanolamine
plasmalogen) and of sphingolipids from white matter. Thus,
the lipid composition of white matter resembles that of gray
matter. The cerebrospinal fluid shows raised phospholipid
levels.
The sphingolipidoses (lipid storage diseases) are a group
of inherited diseases that are caused by a genetic defect in the
catabolism of lipids containing sphingosine. They are part of a
larger group of lysosomal disorders and exhibit several constant
features: (1) complex lipids containing ceramide accumulate
in cells, particularly neurons, causing neurodegeneration and
shortening the life span. (2) The rate of synthesis of the stored
lipid is normal. (3) The enzymatic defect is in the degradation
pathway of sphingolipids in lysosomes. (4) The extent to which
the activity of the affected enzyme is decreased is similar in all
tissues. There is no effective treatment for many of the dis-
eases, although some success has been achieved with enzyme
replacement therapy and bone marrow transplantation in
the treatment of Gaucher and Fabry diseases. Other promising
approaches are substrate deprivation therapy to inhibit the
synthesis of sphingolipids and chemical chaperone therapy.
Gene therapy for lysosomal disorders is also currently under
investigation. Some examples of the more important lipid stor-
age diseases are shown in Table 24–1.
Multiple sulfatase deficiency results in accumulation of
sulfogalactosylceramide, steroid sulfates, and proteoglycans
owing to a combined deficiency of arylsulfatases A, B, and C
and steroid sulfatase. Symptoms include abnormalities in neu-
rologic and metabolic functions, as well as in hearing, sight,
and bone. Metachromatic leukodystrophy is characterized by
a build-up of sulfatides in tissues caused by a defect in arylsul-
fatase A, and leads to irreversible damage to the myelin sheath.
SUMMARY
■ Triacylglycerols and some phosphoglycerols are synthesized
by progressive acylation of glycerol-3-phosphate. The pathway
bifurcates at phosphatidate, forming inositol phospholipids and
cardiolipin on the one hand and triacylglycerol and choline and
ethanolamine phospholipids on the other.
■ Plasmalogens and PAF are ether phospholipids formed from
dihydroxyacetone phosphate.
■ Sphingolipids are formed from ceramide (N-acylsphingosine).
Sphingomyelin is present in membranes of organelles involved
in secretory processes (eg, Golgi apparatus). The simplest
glycosphingolipids are a combination of ceramide plus a sugar
residue (eg, GalCer in myelin). Gangliosides are more complex
glycosphingolipids containing more sugar residues plus
sialic acid. They are present in the outer layer of the plasma
membrane, where they contribute to the glycocalyx and are
important as antigens and cell receptors.
■ Phospholipids and sphingolipids are involved in several
disease processes, including infant respiratory distress
syndrome (lack of lung surfactant), multiple sclerosis
(demyelination), and sphingolipidoses (inability to break
down sphingolipids in lysosomes due to inherited defects in
hydrolase enzymes).