Lipid metabolism II:

Pathways of metabolism of special lipids

Robert H. Glew

Professor Emeritus, University of New Mexico

18.1 Introduction

18.2 Phospholipids

18.3 cholesterol

18.4 sphingolipids

18.5 prostaglandin and thromboxanes

18.6 lipoxygenase and oxyeiocosatetraenoic acids

Clinical correlations

18.1 clearence of red blood cells: role of phosphatidylserine

18.2 respiratory distress syndrome

18.3 treatment of hypercholesterolemia

18.4 atherosclerosis

18.5 diagnosis of gaucher disease in an adult

Key concepts

Most cells synthesize the major glycerophospholipids and sphingolipids from

dietary components and metabolic intermediates. Both are major components of
cells membranes.

Glycerophospholipids have other functions including as components of

plumonary surfactant. Phosphatidylcholine has a role in the HDL-dependent
process that carries cholesterol from peripheral tissues to the liver, and inositol-
containing phospholipids serve as second messengers and as attachment sites
for proteins on the cells surface.

Cholesterol is synthesized from acetyl CoA in a multistep process in which the

syinthesize of mevalonate; catalyzed by HMG-CoA reductase, is the rate-limiting,
regulated step. The reductase is the target of the statin place of cholesterol-
lowering drugs. Cholesterol is the precursor for the syntesize of bile acids and
steroid hormons such as testosterone, estrogen, glucocorticoids, and ,
mineralococorticoids.
Plasma lipoproteins, including HDL, LDL, chylomicrons, VLDL, and a variety of
accessory proteins, transport cholesterol and triacyglycerols in blood. Cholesteryl
ester transferase has an important role in the process. LDL and LDL-receptors are
the major regulatory elements that control the levels of cholesterol in plasma
and tissue.

There are several classes of sphingolipids, including sphingomyelin,

cerebrosides, globosides, gangliosides, and sulfatides. Degradation of
sphingolipids involves lysosomal enzymes: A genetic deficiency of one or more of
these enzymes results in the accumulation of incompletely catabolized
sphingolipids and mucopolysacchardes in tissues.

Arachidonic acid is the precursor of lipid hormones that include prostaglandins,

leukotriens, and lipoxins that mediate various inflammatory phenomena. The key
enzymes in these pathways are cyclooxygenase and lipoxygenase.

18.1 INTRODUCTION

Lipid is general term that describes substances that are relatively water
insoluable and extractable by nonpolar solvents. Complex lipids of humans fall
into two broad categories: (1) neutral, nonpolar lipids, such as triacylgycerols
and cholesteryl esters, and (2) polar lipids, such as phospholipids and
glycolipids. The polar lipids are amphipathic, containing a hydrophilic region in
the same molecule. The hydrophobic and hydrophilic region in the same
molecule. The hydrophobic and hydophilic regions in glycerophospholipids are
bridged by a glycerol moiety and in sphingomyelin and glycosphingolipids by
sphingosine. Triacylglycerol is found primarily in storage sites in adipose tissue,
whereas polar lipids occur primarily in cellular membranes.

Complex lipids have many roles. Besides their function in the structure of
membranes, some glycerophospholipids are required for the activity of
membrane enzymes and inositol-containing phospholipids serve as precursors of
signaling molecules Glycosphingolipids have a role in cell-cell recognition,
phagocytosis, contact inhibition, and rejection of transpanted tissues and organs.
Antigenic determinants of blood groups are primarily glycolipids in nature.
Cholesterol is important in artherosclerosis and various sphingolipids accumulate
in genetic disorders called sphingolipidoses.

The nomenclature and chemistry of lipids is presented in the Appendix.

18.2 PHOSPHOLIPIDS

Two major classes of acyglycerolipids are triacylglycerols and

glycerophospholipids which have as their core the C 3 polyol, glycerol. Two
primary alcohol groups of glycerol are not stereochemically identical, and in the
case of phospholipids, it is usually the same hydroxylgroup esterified to the
phosphate residue. The stereospecific numbering system designates different
hydroxyl groups. In the system, when the structure of glycerol is drawn in the
Fischer projection with the C2 hydroxyl group projecting to the left of the page,
the carbon atoms are numbered as shown in Figure 18.1. when the stereospecific
numbering (sn) system is employed, the prefix sn- is used before the name of
the compound. Glycerophospholipids usually contain a sn-glycerol 3-phospate
moiety. Although each contains the glycerol moiety as a fundamental structural
element, neutral triacylglycerols and charged ionic phospholipids have very
different physical properties and functions.

Phospholipids Contain Phosphatidic Acid Linked to a Base

Phospholipids are polar, ionic lipids composed of 1,2-diacylglycerol and a

phosphodiester bridge that links the glycerol backbone to some base, usually a
nitrogenous one, such as choline, serine, or ethanolamine (Figures 18.2 and
18.3). the most abundant phospholipids in human tissues are phosphatidylserine
(Figure 18.4). at physiologic pH, phosphatidylcoline and
phosphatidylethanolamine have no net charge and exist as dipolar zwitterions,
whereas phosphatidylserine has a net charge of 1, causing it to be an acidic
phospholipid. Phosphatidylethanolamine (PE) is related to phosphatidylcholine in
that trimethylation of PE produces lecithin. Most phospholipids contain more than
one kind of fatty acid per molecule, so that a given class of phospholipids from
any tissue actually represents a family of molecular species. Phosphatidylcholine
(PC) contains mostly palmitic acid (16:0) or stearic acid (18:0) in the sn-1
position and primarily unsaturated 18 carbon fatty acids oleic, linoleic, or alfa-
linoleic in the sn-2 position. Phosphatidylethanolamine has the same saturated
fatty acids as PC at the sn-1 position but contains more of the long-chain
polyunsaturated fatty acids, namely , linoleic acid [18:2(9,12)], arachidonic acid
[20:4(5,8,11,14)], and docosahexanoic acid [22:6(4,7,10,13,16,19)], at the sn-2
position.

Phosphatidyinositol, an acidic phospholipid that occurs in mammalian

membranes (Figures 18.5), is rather unusual because it often contains almost
exclusively stearic acid (18.0) in the sn-1 position and arachidonic acid in the sn-
2 position.

Another phospholipid composed of a polyol polar head group is

phosphatidylglycerol (Figure 18.5), which occurs in relatively large amounts in
mitochondrial membranes and pulmonary surfactant and is a precursor of
cardiolipin. Phosphatidylglycerol and hosphatidylinositol both carry a formal
charge of -1 at neutral pH and are therefore acidic lipids.

Cardiolipin, a very acidic (charge-2) phospholipid, is composed of two molecules

of phosphatidic acid linked together covalently through a molecule of glycerol
(figure 18.6).it occurs primarily in the inner membrane of mitochondria of
metabolically active tissues (e.g., heart muscle) and in bacterial membranes.
Cardiolipin is present in the membrane of Treponema palladium and is tthe
antigen detected in the Wasserman test for syphilis. Barth syndrome is a rare X-
linked mitochondrial disorder caused by a defect in the TAZ gene, which encodes
the protein taffazin which is required for cardiolipin synthesis. Patients with this
inherited disorder exhibit cardiomyopathy, skeletal myopathy, and abnormal
mitochondria.

Phospholipids mentioned so far contain only O-acyl residues attached to glycerol.

O-(1-alkenyl) substituents occur at C1 of the sn-glycerol in phosphoglycerides in
combination with an O-acyl residues esterified to the C2 position; compounds in
this class are known as plasmalogens (Figure 18.7) or plasmenyl lipids. Relatively
large amounts of ethanolamine plasmalogen (also called
plasmenylethanolamine) occur in myelin with lesser amounts in heart muscle
where choline plasmalogen is abundant. The alkenyl moiety is usually 16:0,
18:0, or 18:1(9).