Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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LIPOPROTEINS

J M Ordovas, Tufts University, Boston, MA, USA

Physiology

0001 In the USA, cardiovascular diseases (CVD) affect

about 62 million people. In 1999, almost one million

subjects in the USA died as a consequence of CVD,

which represents 1 of every 2.5 deaths, placing CVD

as the major cause of morbidity and mortality. This is

also becoming true at the global level, especially with

the recent westernization of lifestyles in developing

countries, which has dramatically increased the

prevalence of CVD risk factors in those populations.

Multiple risk factors and biochemical pathways have

been identified with the progression of these diseases.

These include tobacco smoke, dyslipidemias, physical

inactivity, overweight and obesity, diabetes mellitus,

and genetic factors. Several of these risk factors can

be ameliorated by adequate nutritional behavior. In

this article we concentrate on the physiology of

plasma lipoproteins and the impact of nutritional

factors on homeostasis and on the prevention of

dyslipidemias and of CVD.

0002 Lipids (cholesterol, triacylglycerols, and phospho-

lipids) are transported in blood as part of lipoprotein

particles. Lipoproteins are generally spherical par-

ticles, with a shell composed of unsterified cholesterol

and phospholipid with the fatty acids oriented toward

the core of the particle. Included in this shell are

specific proteins known as apolipoproteins. The

core of the lipoprotein particles is made up of choles-

teryl ester and triacylglycerol molecules.

0003The nomenclature and classification of serum lipo-

proteins were originally determined by the laboratory

technique used for their separation or isolation. These

included mainly electrophoretic, ultracentrifuge, and

immunological techniques. Accordingly, lipoproteins

have been classified based on their electrophoretic

mobility, hydrated density, and apolipoprotein com-

position (Table 1). Here, we present a description of

the different lipoprotein particles, their metabolism,

and the consequences of the alterations of their

homeostasis.

Classification of Lipoproteins

Classification of Serum Lipoproteins According to

their Electrophoretic Mobilities

0004With the development of techniques to separate pro-

teins according to their electrophoretic characteris-

tics, it was shown that most of the lipid present in

serum was associated with proteins migrating with

- and b-globulin mobilities. This resulted in the first

classification of lipoproteins according to their colo-

calization with other plasma proteins as a

-and

b-lipoproteins. Development of more advanced elec-

trophoretic techniques resulted in further discrimina-

tion among the lipoprotein classes into b-, pre-b- and

a-lipoproteins. Careful observation of thousands of

electropherograms from normal and dyslipidemic

subjects provided the basis for the first structured

tbl0001 Table 1 Classification and characteristics of human plasma lipoproteins

Lipoprotein Diameter (nm) Density (gml

1

) Electrophoretic mobility Majorlipids Major apolipoproteins

Chylomicrons 80–500 < 0.95 Origin Dietary triacylglycerols

and cholesteryl esters

ApoA-I, ApoA-IV, ApoB-48,

ApoC-I, ApoC-II, ApoC-III,

ApoE

Quilomicron

remnants

> 30 < 1.006 Origin Dietary cholesteryl esters

and triacylglycerols

ApoB-48, ApoE, ApoC-III

VLDL 30–80 < 1.006 Pre-beta Endogenous triacylglycerols ApoB-100, ApoC-I, ApoC-II,

ApoC-III, ApoE

IDL 25–35 1.006–1.019 Pre-beta and beta Endogenous cholesteryl ester

and triacylglycerosls

ApoB-100, ApoE

LDL 18–28 1.019–1.063 Beta Cholesteryl esters ApoB-100

Lp(a) Cholesteryl esters Apo(a), ApoB-100

HDL2 9–12 1.063–1.125 Alpha Cholesteryl esters,

phospholipids

ApoA-I, ApoA-II

HDL3 5–9 1.125–1.210 Alpha Cholesteryl esters,

phospholipids

ApoA-I, ApoA-II

VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); HDL, high-density

lipoprotein.

LIPOPROTEINS 3543

classification of lipoprotein disorders, which is

known as Fredrickson classification (Table 2). This

classification played a pivotal role in the clinical

aspects of lipoprotein metabolism, genetics, and cor-

onary heart disease (CHD). Recently, a more func-

tional approach to the classification of familial

lipoprotein disorders has been made possible thanks

to the advances in the elucidation of the specific gene

loci responsible for some of these disorders.

0005 Several electrophoresis media have been used for

the separation of plasma lipoproteins. These include

liquid, paper, cellulose acetate, agarose, and polya-

crylamide. These techniques were used well into the

1980s by scientists and clinicians as a relatively quick

tool for the assessment of lipoprotein patterns and

dyslipidemias. These techniques, especially agarose

gel electrophoresis, were used for identifying the pres-

ence of what is know as a broad beta band in the

diagnosis of type III hyperlipidemia, a rare genetic

disorder resulting from the presence of specific

mutant forms of apolipoprotein E, primarily Apo E2.

0006 Although, the classification of lipoproteins based

on their electrophoretic behavior has been relegated

to a historical value, the use of electrophoresis as a

separating tool with potential clinical applications

has seen a rebirth in recent years resulting from the

realization that specific lipoprotein subclasses may be

more informative in terms of CHD risk prediction

than the traditional plasma lipid measures. At this

regard, gradient agarose-polyacrylamide gel electro-

phoresis under nondenaturing conditions has been an

essential tool to analyze the heterogeneity of low-

density- (LDL) and high-density lipoprotein (HDL)

subclasses. LDL subclasses can be resolved by non-

denaturing polyacrylamide gradient gel (2–16%) in

up to seven LDL subfractions with densities ranging

from 1.020 to 1.063 g ml

1

and diameters ranging

from 22.0 to 28.5 nm. The individual profiles usually

show a major subclass and several minor ones (one to

four). A predominance of smaller, denser LDL, versus

larger, more buoyant LDL particles in plasma has

been associated with increased CHD risk. The pres-

ence of specific subclasses in serum is determined by a

combination of genetic and nongenetic factors, in-

cluding age, gender, and diet. A significant correlation

has been demonstrated between high triglyceride con-

centrations and the presence of small LDL subclasses.

HDL subclasses have been resolved using similar

techniques, with a polyacrylamide gradient ranging

from 4 to 30%, into five subclasses (HDL3c, HDL3b,

HDL3a, HDL2a, and HDL2b). Improved electro-

phoresis techniques have allowed the resolution of

up to 14 HDL subclasses. The clinical significance

of these subfractions needs further clarification.

However, the current notion is that the presence of

large HDL particles appears to be associated with

protection, whereas small HDL particles are either

neutral or even atherogenic.

Classification of Serum Lipoproteins According to

their Ultracentrifugal Characteristics

0007The presence of lipids within the lipoprotein particles

confers these macromolecular complexes with a lower

density compared with other serum proteins. The

development of ultracentrifugation in the 1940s

allowed their separation from the other proteins

based on this flotation property. Initially separated

just a single discrete peak, it was not long before it

was possible to separate a wide spectrum of particle

sizes and densities (d) ranging from 0.92 to 1.21 g ml

1

0008Lipoproteins were classically separated into four

major subclasses designated as chylomicrons

(exogenous triacyglycerol-rich particles of d < 0.94

gml

1

), very-low-density lipoproteins (VLDL, en-

dogenous triacylglycerol-rich particles of d ¼0.94–

1.006 g ml

1

), LDL (cholesteryl ester-enriched

particles of d ¼1.006–1.063 g ml

1

), and HDL

particles containing approximately 50% protein of

tbl0002 Table 2 Classical classification of hyperlipidemias according to Fredrickson

Total cholesterol Triacylglycerol Lipoprotein(s)

fractionaffected

Atherosclerosisrisk Genetic defect

I Normal to elevated Very elevated Chylomicrons No Familial LPL deficiency Apo C-II deficiency

IIa Elevated Normal LDL High Familial hypercholesterolemia

Familial combined hyperlipidemia

Polygenic hypercholesterolemia

IIb Elevated Elevated LDL and VLDL High Familial hypercholesterolemia

Familial combined hyperlipidemia

III Elevated Very elevated IDL High Familial dysbetalipoproteinemia

IV Normal or elevated Elevated VLDL Moderate Familial hypertriglyceridemia

Familial combined hyperlipidemia

V Normal or elevated Very elevated VLDL and

chylomicrons

Moderate Familial hypertriglyceridemia

LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; Apo C-II, apolipoprotein C-II.

3544 LIPOPROTEINS

d ¼1.063–1.21 g ml

1

)(Table 1). Continued im-

provement of ultracentrifugation equipment and

techniques permitted the resolution of these

major families into several density subclasses such as

HDL2a (d ¼1.10–1.125 g ml

1

), HDL2b (d ¼1.063–

1.10 g ml

1

), and HDL3 (d ¼1.125–1.21 g ml

1

) and

several LDL and VLDL subfractions.

0009 Ultracentrifugation has been essential for the de-

velopment of this field; however, this technique is

very labor-intensive, thus seriously limiting its clinical

and epidemiological applications. Moreover, lipopro-

teins are subjected during long periods of time to a

harsh environment consisting both of high salt con-

centration and g forces. These problems have been

mitigated by the development of small vertical and

near-vertical rotors, which allow shorter runs, while

achieving similar separations.

Classification of Serum Lipoproteins According to

their Apolipoprotein Content

0010 The characterization of plasma apolipoproteins

(Tables 1 and 3) and the elucidation of their physio-

logical function reinforced the notion that the meas-

urement of the apolipoproteins rather than the lipids

in lipoprotein fractions could provide more precise

biochemical prediction of CHD risk. However, so far,

apolipoprotein measurement has not provided a

clear practical advantage over the measurement of

more classical risk factors (total cholesterol (TC),

HDL cholesterol (HDL-C), and LDL cholesterol

(LDL-C)). However, this concept gave a thrust to

the development of methods of separation based on

apolipoprotein composition, namely those based

on immunoaffinity chromatography. By using

columns containing antibodies against specific apoli-

poproteins, several VLDL and HDL subpopulations

can be resolved. More effort has been placed on the

characterization of the HDL subfractions.

0011Lipoproteins containing apoA-I can be separated

into two major species: those containing both apoA-I

and apoA-II, known as LpAI:AII, and those contain-

ing apoA-I but not apoA-II (LpAI). It has been hy-

pothesized that the protective role of HDL for CHD is

relegated to the LpAI particles, whereas the LpAI:AII

fraction may not be protective and could even be

atherogenic. Likewise, lipoproteins containing apoB

consist of four lipoprotein families. Lipoproteins con-

taining apoB only (LpB) are cholesteryl ester-rich and

are found primarily within the LDL density range.

Particles containing both apoB and apoC (LpB:C),

apoB and apoE (LpB:E), and all three apolipoprotein

groups (LpB:E:C) are tryacylglycerol-rich lipopro-

teins (TRL) and are found within the VLDL and

IDL density range.

0012The power of affinity chromatography has been

utilized to separate another lipoprotein fraction

known as lipoprotein(a) (Lp(a)). Lp(a) is a lipoprotein

containing apoB100 as well as an antigenically unique

apolipoprotein (apo(a)). Its separation from other

plasma lipoproteins can be readily accomplished

tbl0003 Table 3 Classification and properties of apolipoproteins

Apolipoprotein Amino acids Chromosomal

localization

Main function

ApoA-I 243 Liver, intestine 11q23 HDL structure, LCAT activator, ligand for HDL binding,

reverse cholesterol transport

ApoA-II 77 Liver 1q21–1q23 HDL structure, LPL and HTGL activity

A-IV 377 Intestine 11q23 LCAT activator, lipid absorption (?)

appetite regulator (?), regulator of LPL activity

A-V 366 11q23 TRL metabolism

Apo(a) Variable Liver 6q27 Lp(a) structure, plasminogen inhibitor (?)

Apo B-48 2152 Intestine 2p24 Chylomicron structure Secretion of chylomicrons

ApoB-100 4536 Liver 2p24 VLDL, IDL, LDL structure, LDL receptor ligand

ApoC-I 57 Liver, intestine 19q13.2 LPL and LCAT activator, inhibitor of LRP (?)

ApoC-II 79 Liver, intestine 19q13.2 LPL activator

ApoC-III 79 Liver, intestine 11q23 LPL inhibitor,

ApoC-IV 127 19q13.2 (?)

ApoD 169 Multiple tissues 3q26.2-qter Closely associated with LCAT (?),

radical scavenger (?)

ApoE 299 Liver macrophages 19q13.2 Ligand for most lipoprotein receptors,

reverse cholesterol transport

APOF 326 12 Lipid transfer inhibitor, CETP inhibitor

ApoH 345 17q23-qter Platelet function (?)

ApoJ 416 8p21-p12 (?)

HDL, high-density lipoprotein; LCAT, lecithin cholesterol acyl transferase; LPL, lipoprotein lipase; HTGL, hepatic triacylglycerol lipase; TRLs

triacylglycerol-rich lipoproteins; CETP, cholesterol ester transfer protein; Lp(a), lipoprotein(a); VLDL, very-low-density lipoprotein; IDL, intermediate-

density lipoprotein; LDL, low-density lipoprotein.

LIPOPROTEINS 3545

using immunoaffinity chromatography or alterna-

tively taking advantage of its specific affinity for

lectin. The latter has been used to develop a new

technique to measure the concentrations of this

atherogenic lipoprotein in clinical laboratories.

Measurement of Lipoprotein Subfractions

using Nuclear Magnetic Resonance (NMR)

Spectroscopy

0013 More recently, NMR spectroscopy is being used to

determine the concentrations of VLDL, LDL, and

HDL subfractions. NMR distinguishes among the

subfractions on the basis of slight differences in the

spectral properties of the lipids carried within

the particles, which vary according to the diameter

of the phospholipid shell. Each profile displays the

concentrations of six VLDL, one IDL, three LDL, and

five HDL subclasses and the weighted-average par-

ticle size of VLDL, LDL, and HDL. The 10 lipopro-

tein subclass categories used were the following: large

VLDL and remnants (80–220 nm), intermediate

VLDL (35–80 nm), small VLDL (27–35 nm), large

LDL (21.3–27.0 nm), intermediate LDL (19.8–

21.2 nm), small LDL (18.3–19.7 nm), large HDL

(8.8–13.0 nm), intermediate HDL (7.8–8.8 nm), and

small HDL (7.3–7.7 nm). Levels of VLDL subclasses

are expressed in units of triglyceride (mg dl

1

), and

those of LDL and HDL subclasses in units of choles-

terol (mg dl

1

). LDL and HDL subclasses distribu-

tions determined by gradient gel electrophoresis and

NMR have also been shown to be closely correlated.

The major advantages of NMR spectroscopy to

measure lipoprotein subclasses are the low sample

requirements, the speed and high throughput of the

technique, and the relatively low cost.

Metabolism of Serum Lipoproteins

(Figure 1)

Metabolism of Lipoproteins Carrying Exogenous

Lipids

0014Although most of our knowledge about the relation

between plasma lipid concentrations and cardiovas-

cular disease comes from studies in the fasting state,

we should keep in mind that, in affluent countries,

humans are postprandial animals. Considering that

the gastrointestinal system is busy with the processing

of an ingested meal for at least 6–8 h and the average

person takes three meals per day, the conclusion is

that for most of the 24 h of a day the intestine is

working. The digestive system works efficiently and

dynamically with the dietary fat, with virtually no

remains of the ingested fat being excreted. This places

the gut as a central organ in lipid metabolism, and

Dietary fat, cholesterol,

and plant sterols

Bile acids

Cholesterol

Sterolins

SRBI

Cholesterol Plant sterol

Liver

LDLR

Remnant-R

Bile acids Cholesterol

LDLR

LDL

Peripheral

tissues

HDL

IDL

VLDL

Chylomicron

remnant

Chylomicrons

LPL

FFA FFA

SRBI

TG and PL

Intestine

ApoB-48

fig0001 Figure 1 Depiction of the exogenous and endogenous lipoprotein metabolism pathways. SRBI, scavenger receptor, class B; TG,

triglycerides; PL, phospholipids; LDLR, low-density lipoprotein receptor; LDL, low-density lipoproteins; VLDL, very-low-density

lipoproteins; IDL, intermediate-density lipoproteins; HDL, high-density lipoproteins; LPL, lipoprotein lipase; FFA, free fatty acids.

3546 LIPOPROTEINS

underlines the importance of postprandial lipidemia.

Postprandial lipid metabolism has received consider-

able attention since it was shown that postprandial

TRL are involved in the development of athero-

sclerosis. Many studies comparing CHD patients

with controls have demonstrated differences in post-

prandial TG after an oral fat load test and that the

postprandial TG concentration is an independent pre-

dictor of CHD in multivariate analysis. A delayed

clearance of retinyl palmitate (RP), used to study the

metabolism of TRL of intestinal origin, discriminates

between patients with CHD and controls, even after

adjustment for fasting TG or HDL-C in normolipi-

demic men. The relation of postprandial lipid metab-

olism to atherosclerosis makes this evaluation a

priority in atherosclerosis research. It is no longer

possible to ignore its importance and to try to explain

the relation between lipids and atherosclerosis exclu-

sively on the basis of the fasting lipid levels. There-

fore, it is of paramount importance to gain a better

understanding about the mechanisms involved in the

metabolism of lipoproteins carrying exogenous (diet-

ary) lipids, primarily triacylglycerols and cholesterol.

It is important to emphasize that, whereas the absorp-

tion of fat is highly efficient and uniform in most

humans, the absorption of cholesterol is highly vari-

able. Therefore, the understanding of this variability

could be applied to the generation of new therapeutic

targets for the reduction of CHD.

0015 Cholesterol has for decades received a bad press

and for most people is just a ‘fat’ in blood that in-

creases the risk of heart disease. However, cholesterol

is essential for the growth and viability of cells in

higher organisms. We have about 100 g of choles-

terol; of those 100 g, about 7 g is found in the blood

circulating as part of lipoproteins, whereas the

remaining 93 g is located in the body cells. The phys-

ical characteristics of cholesterol, with its insolubility

in water and its rigidity, provides cell membranes

with their structural integrity and modulates their

fluidity, thus maintaining an optimal communication

between the cell and its environment, including the

transport of nutrients and the proper maintenance

of energy resources. Another major use of cholesterol

is on the synthesis of bile acids. These are synthesized

in the liver from cholesterol and are secreted in the

bile. They are essential for the intestinal absorption of

fat. Without cholesterol we could not absorb the

essential fatty acids and fat-soluble vitamins A, D,

E, and K from the food. In lesser amounts, cholesterol

is used to synthesize steroid hormones, including

the sex hormones estrogen, progesterone, and testos-

terone as well as the corticosteroids. Cholesterol is

also the precursor from which the body synthesizes

vitamin D.

0016Cholesterol homeostasis is crucial for optimal per-

formance of multiple biochemical pathways, and it is

maintained by a delicate equilibrium between dietary

cholesterol absorption, de novo synthesis, and fecal

excretion. In terms of the de novo synthesis, higher

organisms have developed a complex biosynthetic

pathway for the synthesis of cholesterol, which has

been precisely defined, requiring approximately 30

steps. Conversely, the process of intestinal cholesterol

absorption from foods has been an area of contro-

versy. Many believed this to be a process of passive

diffusion across the brush-border membrane from the

lumen of the gut into the enterocyte. However, evi-

dence exists that points to a highly regulated carrier-

mediated process. The scavenger receptor SR-BI and

the ‘sterolins’ have been implicated in this process and

various apolipoproteins can affect the rate of choles-

terol transfer in vitro.

0017We synthesize approximately 900 mg of cholesterol

per day. In addition, we consume on average

*300 mg of cholesterol per day with the diet. Under

optimal homeostatic conditions, the same amount

(1200 mg day

1

) is excreted as fecal sterols. In terms

of the intestinal cholesterol absorption, the exogen-

ous cholesterol is hydrolyzed to free cholesterol (FC)

by pancreatic lipases secreted into the intestine. Bile

acids solubilize dietary and biliary cholesterol in mi-

celles in the proximity of the brush border of enter-

ocytes, where it diffuses through the epithelial

membrane to the interior of the cell. Our current

knowledge indicates that some of the exogenous chol-

esterol and most of the plant sterols entering the

enterocyte are secreted back to the intestinal lumen

via the recently characterized ABC transporter G5

(ABCG5) and ABC transporter G8 (ABCG8), also

known as ‘sterolins.’

0018In the smooth endoplasmic reticulum, exogenous

cholesterol is converted to cholesteryl ester (CE) by

acyl CoA:cholesterol acyltransferase (ACAT), and

then used by microsomal triglyceride transfer protein

(MTP) to synthesize chylomicrons. These chylomi-

crons are pumped through the thoracic lymph duct

into the blood, where lipoprotein lipase (LPL) hydro-

lyzes them into chylomicron remnants.

0019Chylomicrons and their remnants are heteroge-

neous particles that vary in size, composition, and

metabolism. They transport dietary lipids and are

considered ‘exogenous’ lipoproteins, in contrast to

‘endogenous’ VLDL. Chylomicrons are synthesized

continuously, and may increase in size and cholesterol

content when dietary fat and cholesterol increase.

They have a higher turnover rate than that of LDL

particles and may contribute more cholesterol to

tissues in a 24-h period. Most chylomicron remnants

are rapidly catabolized in the liver after their uptake

LIPOPROTEINS 3547

by specific receptors. In addition, large chylomicron

particles may be metabolized to small remnants

(45 nm) that are similar in size to atherogenic LDL

remnants and may readily penetrate arterial cells via

transcytotic vesicles. Data from animal and human

studies strongly support the concept that chylomicron

remnants may have a dramatic impact on the risk of

atherosclerosis and CHD.

0020 There has been a long and heated debate surround-

ing the use of low-fat, high-carbohydrate diets as the

preferred recommendation to lower CVD risk in the

general population. On one hand, these diets have

been shown to lower plasma TC and LDL-C; how-

ever, on the other hand, in populations leading a

westernized lifestyle, these carbohydrate-rich diets

can simultaneously raise the levels of the (also athero-

genic), TRL and lower HDL-C concentrations. This

leads to the concern that, at least in some individuals,

the beneficial LDL-lowering effect may be offset by

adverse changes in other circulating lipoprotein frac-

tions. This concept is specially relevant following the

demonstration of a significant correlation between

TG levels and the presence of the highly atherogenic

small dense LDL subfraction.

Endogenous Lipoprotein Metabolism

0021 Liver cells can metabolize CE into bile acids or dir-

ectly secrete it into the bile. Bile acids aid in the

formation of micelles, and the secreted cholesterol is

excreted via the feces. Hepatic cells also synthesize

endogenous cholesterol and release VLDL and LDL-

C into the circulation. These molecules are delivered

to peripheral organs for either utilization or storage.

Therefore, the liver is involved in both the uptake of

newly synthesized cholesterol and the export of the

metabolized sterol into the feces through either bile

acid or neutral sterol formation. Consequently, the

liver must respond to variations that occur in both

input and output pathways.

0022 Lowering LDL-C by reducing the intake of satur-

ated fat is one of the cornerstones of the current

dietary recommendations to reduce CHD risk. In

most cases the reduction in saturated fat is accompan-

ied by a parallel reduction in total fat intake. The

reduction of LDL-C following a reduction in satur-

ated fat appears to be mediated by increases in LDL

receptor activity, resulting in enhanced liver LDL

clearance. However, the downside of these recom-

mendations, as previously indicated, lays in the

effects on triglyceride levels and possibly on LDL

subfractions.

0023 Two major LDL subclasses have been defined: type

A and type B. Type A is larger, more buoyant and

apparently less atherogenic. Conversely, type B is

defined as those particles that are smaller, denser,

and more atherogenic. In view of these qualitative

differences in CHD risk, it is very important to exam-

ine the diet-induced changes on each of those sub-

fractions. The current data support the notion that

in asymptomatic subjects carrying the pattern B

phenotype, switching from a high-fat to a low-fat

diet results in significant LDL-C reduction, which is

larger than for those subjects carrying the pattern A

phenotype. Moreover, as expected, the LDL-C reduc-

tion is primarily due to lowering of the small LDL

class and this should result in significant CHD risk

reduction. Conversely, in asymptomatic subjects

carrying the pattern A phenotype, a change from a

high-fat to a low-fat diet results in a shift from buoy-

ant to denser LDL, with very small changes in particle

numbers. This shift may not be associated with a

reduction in CHD risk and may even increase the

atherogenic risk.

Reverse Cholesterol Transport

0024The recent characterization of SRBI as an HDL recep-

tor and the identification of ABCA1 as the membrane

transporter that mediates the efflux of cholesterol

from the cells have pushed forward our under-

standing of HDL metabolism and reverse cholesterol

transport.

0025HDL is synthesized by both the liver and the intes-

tine. Its precursor form is discoidal in shape and

matures in circulation as it picks up unesterified chol-

esterol, and probably phospholipids, from cell mem-

branes by a mechanism mediated by the ABCA1

transporter. Moreover, HDL can also obtain lipids

and apolipoproteins from TRL as these particles

undergo lipolysis. The cholesterol is esterified by the

action of the lecithin cholesterol acyltransferase

(LCAT) and the small HDL3 particle becomes a

larger HDL2 particle. The esterified cholesterol is

either delivered to the liver or to organs synthesizing

steroid hormones, such as the adrenals, via SRBI or

other receptor-independent mechanisms, or trans-

ferred by the action of cholesteryl ester transfer

protein (CETP) to other lipoproteins (such as chylo-

micron, VLDL remnants, or LDL), in exchange for

triacylglycerols. This cholesterol may then be taken

up by the liver via receptors specific for these lipopro-

teins (LDLR, VLDLR, remnant receptor), or it can be

delivered again to the peripheral tissues. The triacyl-

glycerol received by HDL2 is hydrolyzed by hepatic

lipase and the particle is converted back to HDL3,

completing the HDL cycle in plasma. In the liver,

cholesterol can be excreted directly into bile, con-

verted to bile acids, or reutilized in lipoprotein

production.

3548 LIPOPROTEINS

0026 Diets high in simple carbohydrates reduce HDL

cholesterol concentrations. This effect appears to be

mediated by increases in the catabolism of apoA-I;

however, it has also been proposed that decreases in

apoA-I production contribute to this effect.

Disorders of Lipoprotein Metabolism

0027 Many of the major advances in our knowledge of

lipoprotein metabolism and physiology have been

driven by the study of abnormalities. As indicated

above, familial lipoprotein disorders were first classi-

fied according to their different electrophoretic pro-

file. This classification was successfully used for

decades; however, it had shortcomings. One of them

was that it included under the same denomination

diseases with different molecular basis. Another one

was that some important phenotypes (i.e., familial

hypoalphalipoproteinemia) were not part of the ori-

ginal classification. The elucidation of the molecular

mechanisms responsible for several of these syn-

dromes has allowed a more functional classification,

based on the genetic loci influencing the phenotypes.

Below, a brief summary of the most common or rele-

vant familial lipoprotein disorders is presented.

Familial Hypercholesterolemia

0028 Familial hypercholesterolemia (FH), also known as

FHC, and according to the original Fredrickson

classification as hyperlipoproteinemia type IIa, is an

autosomal dominant disorder characterized by dra-

matic elevations of plasma LDL cholesterol concen-

trations. The locus responsible for this disorder is the

low-density lipoprotein receptor (LDLR) in chromo-

some 19. The LDLR gene family consists of cell

surface proteins involved in receptor-mediated endo-

cytosis of specific ligands. LDL is normally bound at

the cell membrane and taken into the cell, ending up

in lysosomes where the protein is degraded and the

cholesterol is made available for repression of micro-

somal enzyme 3-hydroxy-3-methylglutaryl coenzyme

A (HMG CoA) reductase, the rate-limiting step in

cholesterol synthesis. At the same time, a reciprocal

stimulation of cholesterol ester synthesis takes place.

Hundreds of mutations have been identified at

the LDLR locus, resulting in the FH phenotype. The

global frequency of FH is about 1 in 500 in the

heterozygous state and 1 in a million in the homozy-

gous state. However, this varies considerably and

there are places like the province of Quebec where

the frequency of FH is much higher.

0029 The ranges of LDL-C concentrations in the plasma

of heterozygous FH are 200–400 mg dl

1

,whereasin

homozygotes the LDL-C concentrations range between

400 and 1000 mg dl

1

. The clinical characteristics

observed in heterozygotes include tendinous xantho-

mas, corneal arcus, and CHD in the 40s and 50s.

In homozygotes, there is also the presence of planar

xanthomas and the clinical manifestation of the disease

is more premature.

0030Inhibitors of HMG CoA, a key enzyme in the syn-

thesis of cholesterol, are the drugs of choice in the

treatment of heterozygotes FH. Most pharmaco-

logical therapies are ineffective in the homozygous

state. These subjects may be treated with LDL apher-

esis, liver transplant, and, based on some preliminary

results, in the future, these subjects could be excellent

candidates for gene therapy. Diet and lifestyle modi-

fication are also recommended and in some cases may

be highly effective. This is supported by the fact that

the phenotypic expression of some of the LDLR mu-

tations is not expressed in populations living a trad-

itional, healthy lifestyle, but it is expressed in those

subjects living in societies with a more westernized

lifestyle. The impact of modernization on the clinical

expression of the disease has also been demonstrated

by studying mortality during the last 200 years in a

large pedigree with a well-characterized LDLR ab-

normality. In these subjects the presence of the muta-

tion did not manifest as premature death until the

middle of the twentieth century, suggesting that life-

style could play a relevant role in the clinical expres-

sion of this phenotype. Moreover, we are starting to

identify some other genetic factors that can modulate

the biochemical and clinical manifestation of the

phenotype: gene-by-gene interactions.

0031There are other forms of hypercholesterolemia that

are not due to defects on the LDLR. One of them

produces similar biochemical phenotypes and it has

been named familial defective apoB-100. This disease

is also autosomal dominant. The frequency of this

disorder has not been well elucidated and it varies

considerably depending on the ethnicity of the popu-

lation studied, as it appears to have a central Euro-

pean origin. The locus responsible for this phenotype

is the apolipoprotein B (Apo B) in chromosome 2 and

the specific defect is a point mutation that changes

the amino acid 3500 of the mature apoB

(ARG3500GLN). It has been shown that the argin-

ine-3500 interacts with tryptophan-4369 in the

carboxyl tail and facilitates the conformation of

ApoB-100, required for normal receptor binding of

LDL. Disruption of this conformation prevents the

normal binding of LDL to its receptor, resulting in the

observed hypercholesterolemia.

0032The genetic defects associated with the common

forms of hypercholesterolemia present in subjects

with cholesterol levels between 250 and 300 mg dl

1

have not been elucidated. These are, most probably,

due to a combination of predisposing alleles (i.e., the

LIPOPROTEINS 3549

presence of the E4 allele at the Apo E locus) with

environmental factors (i.e., diet, physical inactivity,

smoking, obesity). This ‘garden variety’ of mildly

severe hypercholesterolemia is also known as poly-

genic hypercholesterolemia.

Familial Dysbetalipoproteinemia

0033 This disorder is characterized by simultaneous in-

creases in plasma cholesterol and tryglyceride concen-

trations. The locus responsible for this familial

disorders is the Apo E gene in chromosome 19. The

most common genetic defect is the presence of the E2

(arg158-to-cys) allele. Other less common mutations

include the E2 (lys146-to-gln), E2 (arg145-to-cys)

and E2-Christchurch (arg136-to-ser). In most pa-

tients, the complete expression of the clinical pheno-

type needs additional interactions with age, obesity,

and diabetes, as well as other genetic loci. In addition

to the accumulation in plasma of VLDL and chylo-

micron remnants, other clinical features of this dis-

order are tuboeruptive and, in some cases, planar

xanthomas. Therapies include diet and hypolipidemic

agents such as fibrates, statins, or nicotinic acid. In

most cases, diagnosis can be carried out first by lipo-

protein electrophoresis, followed by the molecular

elucidation of the Apo E defect.

Familial Combined Hyperlipidemia

0034 Familial combined hyperlipidemia (FCHL) was ini-

tially described as the combination of hypercholester-

olemia and hypertriglyceridemia within the same

kindred, and with kindred members having one of

these abnormalities or both. Moreover, most subjects

with FCHL have HDL-C concentrations below the

10th percentile. In addition, predominance of small

dense LDL particles and elevated apolipoprotein B

levels is commonly found in members of FCHL fam-

ilies. This disorder has a frequency of approximately

10% in survivors of premature myocardial infarction

(less than 60 years of age) and about 14% in kindred

with CHD.

0035 Given the high frequency and the clinical implica-

tions of this disorder, there has been an intense search

for the molecular and genetic defect(s) responsible

for this phenoype. It has been reported that affected

subjects have overproduction of ApoB-100, and

several chromosomal regions have been associated

with this defect, including 2p, 11p, 16q, and 19q, as

well as mutations at several candidate genes (LPL,

ApoA1-ApoC3-ApoA4). The expression of this

disorder may be triggered by other factors such as

overweight, hypertension, diabetes, and gout. The

treatment should include diet and physical activity

and, if necessary, statins or fibrates, depending on

the major lipid present in excess.

0036Another common biochemical syndrome associ-

ated with increased CHD risk is familial hyperapobe-

talipoproteinemia, which has been suggested to be a

variant of FCHL. Hyperapobetalipoproteinemia is

characterized by ApoB values above the 90th percent-

ile in the absence of other lipid abnormalities. There-

fore, there will be an increased number of small,

dense LDL particles. The gene(s) responsible for

this disease has not been elucidated; however, there

is evidence showing the Mendelian inheritance

and the etiologic heterogeneity of the hyperapoB

phenotype.

Familial Hypoalphalipoproteinemia

0037Severe HDL deficiency, characterized by HDL-C con-

centrations < 10 mg dl

1

, is rare and may be due to

Tangier disease (TD), ApoAI, and LCAT deficiencies.

The ApoAI deficiency states are due to rare deletions,

rearrangements, or point mutations within the

ApoA1 locus. Familial hypoalphalipoproteinemia

(FHA) is relatively common and is characterized by

HDL-C concentrations below the 10th percentile of

normal. These subjects have been reported to have

either decreased HDL production or increased HDL

ApoAI catabolism. This phenotype is present in about

4% of kindred with premature CHD.

0038A major recent breakthrough in relation to this

phenotype has been the identification of ABC1 as

the gene for TD and for some cases of FHA. This

finding opens enormous opportunities for the lipo-

protein field and for CHD therapy. The metabolic

pathways determined by the product of the ABCA1

gene will contribute to our understanding of reverse

cholesterol transport and its regulation by dietary fat

and cholesterol. It remains to be elucidated whether

common mutations at this locus are associated with

altered HDL-C levels in the population. This infor-

mation will determine the full impact of the ABCA1

gene in controlling cholesterol efflux and HDL me-

tabolism in the general population, beyond those

affected by TD or FHA. This information will be

applied to the genetic screening of subjects at high

risk for CHD and it could provide us with new thera-

peutic targets, thus increasing our ability to prevent

and treat CHD.

Familial Hypertriglyceridemias

0039Several familial disorders share the phenotype

characterized by high TRLs. The initial classification

distinguished three distinct categories: type I, IV, and

V. The genetic basis has been elucidated only for type

I hyperlipidemia, also known as chylomicronemia,

familial LPL deficiency, or ApoC-II deficiency. As its

name suggests, chylomicronemia is characterized by

3550 LIPOPROTEINS

greatly elevated concentrations of exogenous triacyl-

glycerols and it is the result of impaired lipolysis of

chylomicrons due to a deficiency of LPL of its activa-

tor, the ApoC-II. Several genetic mutations at the LPL

and APOC2 genes have been reported. These are

autosomal recessive traits. In the heterozygous state,

subjects have normal to slightly elevated plasma tri-

glycerides, whereas homozygotes have triacylglycerol

levels that may exceed 1000 mg dl

1

in the fasting

state. The diagnosis of the homozygous state takes

place during the first years of life from the presence of

recurrent abdominal pain and pancreatitis. Eruptive

xanthomas and lipemia retinalis also occur.

0040 The recommended treatment includes a diet low in

simple carbohydrates and with a fat content below

20% of total energy. The use of medium-chain trigly-

cerides (MCT) has also been reported to be effica-

cious. Body weight should be maintained within

normal limits and alcohol consumption should be

avoided.

0041 Fasting chylomicronemia has not been clearly

associated with increased risk for atherosclerosis,

but homozygous subjects are at very high risk for

pancreatitis. However, there is considerable evidence

supporting the atherogenic properties of chylomicron

remnants.

0042 Familial type IV and type V hypertriglyceridemias

may have some overlapping phenotypes. In type IV or

familial endogenous hypertriglyceridemia, triacylgly-

cerol, specifically VLDL concentrations, is increased,

even on a regular diet, and HDL is usually decreased.

This disorder appears to be autosomal dominant and

relatively frequent in populations consuming high-fat

diets. The precise molecular defect(s) has not been

identified; however, the increase in triacylglycerol is

associated with overproduction of triacylglycerol by

the liver and often with the subsequent reduced clear-

ance. Precocious atherosclerosis, abnormal glucose

tolerance, and atheroeruptive xanthoma may occur.

The disorder is undoubtedly heterogeneous and the

phenotype is strongly influenced by environmental

factors, particularly carbohydrate and ethanol con-

sumption.

0043 Other conditions causing hyperlipoproteinemia IV

are uremia, hypopituitarism, contraceptive steroids,

and glycogen storage disease I. Diet should be the first

step in therapy, followed if necessary by pharma-

cotherapy using fibrates.

0044 Type V hyperlipidemia is a much rarer dis-

order associated with increased susceptibility to

atherosclerosis. Usually the first signs of this abnor-

mality are abdominal pain or pancreatitis. VLDL

concentrations are high and chylomicrons are present

in the fasting states. This abnormality has not been

linked to any specific molecular defect.

Familial Lipoprotein(a) Excess

0045Lipoprotein(a) (Lp(a) ) is an LDL particle with one

molecule of Apo(a) attached to it. Elevated levels of

Lp(a) (> 35–40 mg dl

1

or 90th percentile) have been

associated with premature CHD. This increased risk

appears to result from two different mechanisms:

cholesterol deposition in the arterial wall and inhib-

ition of fibrinolysis.

0046Lp(a) concentrations are highly variable; however,

they are relatively constant during a person’s lifetime.

Between 80 and 90% of the variability appears to

be of genetic origin, owing, for the most part, to

variations at the structural Apo(a) gene locus. Lp(a)

concentrations are inversely associated with a size

polymorphism of Apo(a). This polymorphism is due

to differences in the number of a multiple repeat of a

protein domain highly homologous to the kringle 4

domain of plasminogen. Diets and medications used

to lower LDL-C do not appear to have a significant

effect on Lp(a) concentrations. However, niacin has

been reported to decrease Lp(a) concentrations.

There is some evidence suggesting that diets high in

trans fatty acids have a significant raising effect on

Lp(a) concentrations, whereas n-3 fatty acids and

estrogen replacement therapy lower Lp(a) concentra-

tions in the general population and in postmeno-

pausal women, respectively.

Current Guidelines for Dietary Prevention of CHD

0047The cardiovascular benefit from lowering LDL-C

with diet or drug therapies in the general population

and in patients with hyperlipidemia or CHD has been

shown in many population and clinical studies. In

general, dietary therapy includes using diet restricted

in total fat, but more specifically saturated fat

(< 7% of calories) and cholesterol (< 200 mg day

1

)

(Table 4). Pharmacological therapies include primar-

ily statins and fibric acid derivatives. Clinical studies

have shown that both families of drugs lower CHD

and total mortality. However, there is great hetero-

geneity in the way humans respond to any therapeutic

approach, often requiring empirical strategies to find

the appropriate diet, behavioral or drug class and

dose for each patient. Nutrigenetics and pharmaco-

genetics provide the experimental basis to understand

the current unpredictability in response to diet and

drugs as a function of the genetic variability. Some of

the evidence for the genetic basis of this phenomenon

came from the seminal observations showing differ-

ences in drug responses and drug metabolism by sub-

jects from different ethnic groups, suggesting that

genetic factors, underlying ethnicity, were responsible

for those effects. The formal emergence of pharma-

cogenetics as a new field of experimental science took

LIPOPROTEINS 3551

place during the 1960s and over the past 40 years

there has been great progress in understanding the

molecular basis of drug action and in elucidating

genetic determinants of disease pathogenesis and

drug response. More recently, with a better under-

standing of the human genome and the technical

developments in molecular biology as well as in

statistics, we are moving towards larger and more

complex studies, which may involve multiple genes,

gene-by-gene and gene-by-environment interactions.

This knowledge should attain the much searched goal

of providing each subject at risk with the most effect-

ive dietary, behavioral, or pharmacological therapy to

reduce the risk of disease.

Acknowledgments

0048 Supported by NIH/NHLBI grant no. HL54776,

NIH/NHLBI contract no. 1-38038, and contracts

53-K06-5-10 and 58-1950-9-001 from the US De-

partment of Agriculture Research Service.

See also: Cholesterol: Properties and Determination;

Absorption, Function, and Metabolism; Factors

Determining Blood Cholesterol Levels; Role of

Cholesterol in Heart Disease; Coronary Heart Disease:

Prevention; Spectroscopy: Nuclear Magnetic Resonance