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Lipids III: Plasma Lipoproteins

F IG U R E 2 0 -4

Conversion of very-low-density lipoproteins (VLDLs) to low-density lipoproteins (LDLs), via intermediate-density

lipoproteins (IDLs) (the endogenous pathway of lipid transport). Ox-LDL = Oxidized LDL.

is primarily a surface component in these particles, its

secretion would be reduced. If the fatty acid flux to the

liver is large, the process of secretion of triacylglycerols in

VLDLs can become saturated. The resulting triacylglyc-

erol deposition in cytoplasmic droplets is seen in “fatty

liver.”

A high-carbohydrate diet results in substantial elevation

of plasma VLDL concentration. A high-cholesterol diet

alters the composition of VLDL, with cholesterol esters

substituting for triacylglycerol as core components, and

leads to a marked increase in apo E synthesis.

Like nascent chylomicrons, newly secreted VLDL un-

dergoes changes in the plasma (Figure 20-4). Nascent

VLDL acquires apo C and E from HDL. In chylomi-

crons, the apo B is B-48, whereas in VLDL only B-100

is found. LDL contains exclusively apo B-100, indicating

that VLDL rather than chylomicrons is the principal pre-

cursor of LDL. In some species (e.g., the rat), most VLDL

remnants, like chylomicron remnants, are rapidly taken up

by the liver. In humans, as the core triacylglycerols are re-

moved and the C apoproteins are lost, approximately half

of the VLDL is rapidly removed by the liver via the apo B-

100-E receptor pathway. The rest remains in circulation as

VLDL remnants. Since some of these remnants have a den-

sity between 1.006 and 1.019, they are called IDLs and are

analogous to chylomicron remnants. Thus, the liver plays a

major role in clearing remnant lipoproteins. The remaining

IDL are subjected to further catabolism by hepatic lipase

to produce LDL, a cholesterol-rich particle containing al-

most exclusively apo B-100. In cholesterol-fed animals,

including humans, a lipoprotein in the VLDLs density

range is formed that shows pre-/3 mobility on electrophore-

sis. These cholesterol-rich VLDL contain high concentra-

tions of apo E and apo B-48, indicating their intestinal ori-

gin. They are removed from the circulation by a specific

/3-VLDL receptor found on macrophages and endothelial

cells. By promoting cholesterol storage in macrophages,

/LVLDL may play an important role in the formation of

macrophage-derived foam cells found in atherosclerotic

plaques.

Since LDL is the principal plasma-cholesterol car-

rier and its concentration in plasma correlates positively

with the incidence of coronary heart disease, LDL is the

most intensively studied plasma lipoprotein. Production

in humans, via the pathway VLDL —»■

IDL —» LDL,

accounts for all of the LDL normally present. However,

in familial hypercholesterolemia or on a high-cholesterol

diet, VLDL is produced that is higher in cholesterol

content, smaller in size, and within the LDL density range

(1.019-1.063 g/mL).

As IDL loses apo E and is converted to LDL with apo

B-100 as its sole apoprotein, the residence of LDL in

plasma increases from several hours to 2.5 days. This long-

lived, cholesterol-rich LDL serves as a source of choles-

terol for most tissues of the body; although most cells

can synthesize cholesterol under normal conditions, most

endogenous production occurs in the liver and intestine,

from which it is distributed to peripheral tissues by LDL.

This arrangement provides an efficient balance between

endogenous production and dietary intake of cholesterol.