12,13

VERY LOW DENSITY LIPOPROTEINS

VLDLparticles are formed in the liver (Fig. 8-1). Free fatty acids are taken up by the

hepatocyte where the enzyme diglycerol acyltransferase (DGAT) catalyzes TG

formation from diacylglycerol and the coenzyme AcylCoA. The enzyme microsomal

triglyceride transfer protein (MTP) lipidates apoprotein B by transfer of cholesteryl

esters (CE) and TG to form VLDL, which is then secreted by the liver into the

circulation. Inhibitors of MTP reduce production of VLDL and downstream IDL and

LDL. One of these agents, lomitapide, is currently approved for the treatment of the

homozygous form of FH.

14 DGAT inhibitors which reduce TG synthesis are currently

under investigation for management of obesity and hypertriglyceridemia.

15

VLDL particles normally contain 15% to 20% of the total blood cholesterol

concentration and most of the total blood TG concentration. The concentration of

cholesterol in these particles is approximately one-fifth of the total TG concentration;

thus, if the total TG concentration is known, the VLDL-cholesterol (VLDL-C) level

can be estimated by dividing total TGs by 5. Newly secreted VLDL particles are too

large to migrate into the arterial wall and appear to play only a small role in the

pathogenesis of atherosclerosis.

Figure 8-3 Basic structure of lipoproteins. Lipoproteins vary in the amount of cholesterol esters and triglyceride

content. Additionally, they have varying numbers and types of surface apolipoproteins.

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Table 8-1

Classification and Properties of Plasma Lipoproteins

12

Lipoprotein Origin

Density

Range

(g/mL)

Size

(nm)

Cholesterol

Concentration

in plasma

(mmol/L)

a

Triglyceride

Concentration

in plasma

(mmol/L)

b

Major

Apolipoprotein

Other

Apolipoprotein

Chylomicrons Intestine <0.95 100–

1,000

0.0 0 B-48 A-I, C

VLDL Liver <1.006 40–

50

0.1–0.4 0.2–1.2 B-100 A-I, C

IDL VLDL 1.006–

1.019

25–

30

0.1–0.3 0.1–0.3 B-100

LDL IDL 1.019–

1.063

20–

25

1.5–3.5 0.2–0.4 B-100

HDL Tissues 1.063–

1.21

6–10 0.9–1.6 0.1–0.2 A-I A-II, A-IV

Lp(a) Liver 1.051–

1.082

30–

50

B-1, (a)

aFor mg/dL, multiply by 38.67.

bFor mg/dL, multiply by 88.5.

HDL, high-density lipoprotein; IDL, immediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein A;

VLDL, very low-density lipoprotein.

With kind permission from Springer Science+Business media: Genest J. Lipoprotein disorders and cardiovascular risk.

J Inherit Metab Dis. 2002;26:267–287.

VERY LOW DENSITY LIPOPROTEIN REMNANTS

In the circulation the enzyme lipoprotein lipase (LPL) hydrolyzes TGs in VLDL

particles. The removed TGs are converted to fatty acids and stored as an energy

source in adipose tissue. As TGs are removed, the VLDL particle becomes

progressively smaller and relatively more cholesterol rich. The particles formed

through this process include small VLDL particles (called remnant VLDL),

intermediate-density lipoproteins (IDL), and LDL (Fig. 8-5). Approximately 50% of

the remnant VLDL and IDL particles are removed from the systemic circulation by

LDL or apolipoprotein (apo) B-100/apo E receptors on the surface of the liver; the

other 50% are converted into LDL particles by further hydrolytic action of hepatic

lipase. VLDL remnant particles are found in the arterial wall, though in smaller

numbers than LDL. Drugs that enhance the activity of LPL, such as the fibrates,

increase hydrolysis of TG in VLDL particles and lower blood TG levels.

LOW-DENSITY LIPOPROTEINS

LDL particles are cholesterol enriched and carry 60% to 70% of the total blood

cholesterol. LDLplays a central role in the pathogenesis of atherosclerosis and is the

primary target of lipid-lowering therapy. Approximately half of the LDLparticles are

removed from the systemic circulation by the liver; the other half may be taken up by

peripheral cells or deposited in the intimal space of coronary, carotid, and other

peripheral arteries, where atherosclerosis can develop. The probability that

atherosclerosis will develop is directly related to the concentration of LDL-C in the

systemic circulation and the duration of exposure to elevated LDL-C levels; thus, the

cumulative risk of ASCVD in men and women with hypercholesterolemia increases

with age.

HIGH-DENSITY LIPOPROTEINS

HDL particles transport cholesterol from peripheral, lipid-rich inflammatory cells in

the arterial wall back to the liver, a process called reverse cholesterol transport.

16

In

epidemiologic studies HDL cholesterol (HDL-C) concentrations are inversely

associated with the risk of ASCVD, presumably because cholesterol is being

removed from vascular tissue and is not available to contribute to atherogenesis. In

peripheral cells, the adenosine triphosphate binding cassette transporter A-1

(ABCA-1) and adenosine triphosphate binding cassette transporter G-1 facilitate the

efflux of both cholesterol and PLs to apo A1 to form nascent HDL particles.

Cholesterol acquired from peripheral cells by HDL particles is converted into an

esterified form through the action of the enzyme lecithin-cholesterol acyl transferase

(LCAT). HDL particles may either transport cholesterol directly to the liver through

interaction with the scavenger receptor, SR-B1, on the surface of hepatocytes or

transfer it to circulating remnant VLDLand LDLparticles by the action of cholesterol

ester transfer protein (CETP). CETP transfers cholesterol from HDL particles to

VLDL and LDL in exchange for TGs, making the HDL particle less cholesterol rich.

If the latter occurs, cholesterol may be returned to the liver for clearance from the

circulation or delivered back to peripheral cells. Patients have been identified who

have a deficiency of CETP and high plasma concentration of HDL-C which appears

to be associated with a low incidence of CHD. Drugs that inhibit CETP can raise

HDL-C levels and are being studied in long-term cardiovascular outcomes trial.

17

Figure 8-4 Relative lipoprotein sizes and densities.

13 Relative lipoprotein particle densities: In general, a subclass

distribution of increased small LDL, decreased large HDL, and increased large VLDL particle size is most

associated with increased CHD risk. Reprinted with permission from Bays H, Stein EA. Pharmacotherapy for

dyslipdaemia—current therapies and future agents. Expert Opin Pharmacother. 2003;4:1901–1938.

p. 103

p. 104

Figure 8-5 The lipoproteins, apolipoproteins, and enzymes involved in the transport of cholesterol and triglycerides.

HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, verylow-density lipoprotein; HDLN, nascent high-density lipoprotein; HL, hepatic lipase; LL, lipoprotein lipase; CETP,

cholesterol ester transfer protein; LCAT, lecithin cholesterol acyltransferase; B-100, apolipoprotein B-100; C,

apolipoprotein C; E, apolipoprotein E; AI, apolipoprotein AI; AII, apolipoprotein AII; Lp(a), lipoprotein (a).

NON–HIGH-DENSITY LIPOPROTEIN CHOLESTEROL

Though elevated LDL-C is most commonly associated with ASCVD risk, in some

patients the assessment of LDL-C alone may underestimate the risk of events. Non–

HDL cholesterol (non–HDL-C), calculated by subtracting HDL-C from TC, provides

a measure of cholesterol carried by all potentially atherogenic particles, including

VLDL, VLDL remnants, IDL, and LDL particles. Also, in the presence of

postprandial hypertriglyceridemia the calculation of LDL-C may be inaccurate,

whereas non–HDL-C is reliable when measured in the non-fasting state.

CHYLOMICRONS

Unlike the lipoproteins that transport cholesterol from the liver to peripheral cells

and back (endogenous lipid transport), chylomicrons transport TGs and cholesterol

derived from the diet or synthesized in the enterocytes from the gut to the liver

(exogenous lipid transport) (Fig. 8-5, Table 8-1). Chylomicrons are large, TG-rich

lipoproteins. As they pass through capillary beds on the way to the liver, some of the

TG content is removed through the action of LPL in a manner similar to that

described for hydrolysis of TGs from VLDL particles. In the rare individual who has

LPL deficiency, chylomicrons are inefficiently metabolized and TG levels in the

blood may become severely elevated (e.g., 1,000–5,000 mg/dL).

After a fatty meal the number of TG-rich chylomicron particles is elevated and TG

levels rise. Following a 10- to 12-hour period of fasting, chylomicrons will be

removed from the blood by LPL-mediated hydrolysis of TGs and removal of

chylomicron remnants in the liver. TG concentrations measured in the fasting state

reflect primarily TGs that are produced by the liver as well as TGs carried in VLDL

and other remnant particles. For this reason, most patients are asked to fast before a

lipoprotein profile is obtained. A blood sample that is rich in chylomicrons (and to a

lesser extent VLDLparticles) appears turbid; the higher the TG level, the more turbid

the sample. If the sample from a patient with hyperchylomicronemia is refrigerated,

chylomicrons will float to the top and form a frothy white layer, whereas smaller

VLDL particles stay suspended below.

Apolipoproteins

Each lipoprotein particle contains proteins on the outer surface called

apolipoproteins (Fig. 8-5, Table 8-1). These proteins serve four main functions: (a)

they serve as major structural components of lipoproteins, (b) they serve as cofactors

for activation of enzyme systems, (c) they act as ligands for binding to receptors on

cell surfaces, and (d) they are required for assembly and secretion of lipoproteins.

15

Abnormal metabolism of apolipoproteins can

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p. 105

result in faulty enzyme activity or cholesterol transport and an increased risk of

atherosclerosis. Clinicians may consider assessment of blood levels of

apolipoproteins to evaluate dyslipidemic patients, especially those who have a

family history of premature CHD. The five most clinically relevant apolipoproteins

are B-100, C, E, A-I, and A-II.

VLDL particles contain apo B-100, E, and C (Fig. 8-5). The B and E proteins are

ligands for LDL receptors (also called B-E receptors) on the surface of hepatocytes

and peripheral cells. Linkage allows the transfer of cholesterol from the circulating

lipoprotein into the cell through absorptive endocytosis and cellular uptake of the

particle. Defects in these proteins reduce the ability of lipoproteins to bind with

receptor proteins and may result in defective clearance of lipoproteins from the

systemic circulation and increased levels of circulating cholesterol.

Apo C-II is a cofactor or activator of LPL. By activating LPL, apo C-II stimulates

the hydrolysis of TGs from lipoprotein particles in the capillary beds. Deficiency of

apo C-II may result in faulty TG metabolism and subsequent hypertriglyceridemia.

Apo C-III downregulates LPLactivity and interferes with the hepatic uptake of VLDL

remnant particles. This leads to increased concentrations of small VLDL remnant

particles, which are small enough to penetrate into the arterial wall and contribute to

atherogenesis. Apo C-III is a marker of atherogenic dyslipidemia (elevated TGs,

reduced HDL-C, near normal levels of LDL-C, and elevated LDL particle

concentration), which is associated with an increased risk of ASCVD events. In

addition, prolonged residence of VLDL and LDL particles in the systemic circulation

results in the formation of small, highly atherogenic LDL particles and the

atherogenic dyslipidemia (see below).

18

Each VLDL, IDL, and LDL particle contains one molecule of apo B-100. Thus, the

blood concentration of apo B-100 is an indication of the total number of VLDL,

VLDL remnant, IDL, and LDL particles in the circulation. An increased number of

lipoprotein particles and an increased apo B-100 concentration are strong predictors

of ASCVD risk.

19 Remnant VLDL particles retain both apo B-100 and E during the

delipidization process; LDL particles contain only apo B-100 (Fig. 8-5). Some

patients have high levels of apo B-100 suggesting an increased number of atherogenic

particles in the circulation, even though the LDL-C level is in the desirable range.

These patients have an increased risk of atherosclerosis. Apo B-100 and the

measurement of LDL particle concentrations by nuclear magnetic resonance

spectroscopy are considered as recommended treatment targets by some guidelines

for the management of dyslipidemia.