Introduction to Human Nutrition

102 Introduction to Human Nutrition

and CHD risk in prospective cohort studies. The
activity of the HDL pathway is infl uenced by genetic
and dietary factors that can interact to either increase
or reduce the effi ciency of cholesterol removal. This,
in turn, may be refl ected in changes in the concentra-
tion of serum HDLs and their functional properties.
HDLs are synthesized in the gut and liver, and
increase their particle size in the circulation as a result
of the acquisition of cholesterol from two principal
sources: (1) surface material released from TAG-rich
lipoproteins during lipolysis and (2) peripheral
tissues. The particles, which are responsible for
removing cholesterol from cells, are very small pre-
HDLs and are disk-shaped particles composed of
phospholipid and apoA-I (ApoA-I is capable of this
function on its own). The effl ux of free cholesterol
from tissue sites, including deposits of cholesterol in
the coronary arteries, is facilitated by the formation
of a free cholesterol gradient from the cell across the
cell membrane to pre-HDLs. The gradient is gener-
ated by the re-esterifi cation of free cholesterol by the
enzyme lecithin–cholesterol acyltransferase (LCAT)
and via the migration of these newly formed choles-
terol esters into the hydrophobic core of what becomes
mature, spherical HDL. The newly acquired choles-
terol is transported back to the liver either directly by
HDL or indirectly by transfer to apoB-containing
lipoproteins VLDL and LDL. Blood vessels in the liver
contain a close relative of LPL, i.e., HL. This enzyme
acts on smaller lipoproteins and especially the surface

phospholipid of HDL, where it effectively punches

a hole in the surface coat to facilitate access to the

lipid core and delivery of CE to the hepatocyte

(Figure 6.9).

Interrelationships among serum

triacylglycerols and low- and

high-density lipoproteins

Lipids are constantly moving between lipoprotein

particles. This movement is not totally random but

infl uenced by the relative lipid composition of the

lipoproteins and by specifi c lipid transfer proteins

(LTPs) that act as lipid shuttles. In a normal, healthy

individual, TAG-rich lipoproteins transfer TAG to

LDL and HDL in equimolar exchange for CE. This is

mediated through an LTP called cholesteryl transfer

protein (CETP). In this way, CEs are transferred from

HDL to VLDL for passage back to the liver. Conversely,

when the concentration of serum TAG and thus TAG-

rich lipoproteins is increased, for example by either

the overproduction of TAG in the liver or the impaired

removal of TAG by LPL, the result is a net transfer of

TAG into LDL and HDL. As LDL and HDL are over-

loaded with TAG they become favored substrates for

the action of HL and are remodeled into smaller and

denser particles. While small, dense HDL is catabo-

lized rapidly in the liver, lowering serum HDL and

impairing reverse cholesterol transport, small, dense

LDLs are removed less effectively by LDL receptors

and accumulate in serum. Small, dense LDL, by virtue

Peripheral tissues

(including lesions)

Free

Pre--HDL

LCAT

HDL 3

HDL 2

CETP

Hepatic

lipase

LPL

CE

CE

Liver

LDL VLDL

cholesterol

Figure 6.9 Reverse cholesterol trans-

port. CE, cholesterol ester; CETP, choles-

terol ester transfer protein; HDL,

high-density lipoprotein; LCAT, lecithin–

cholesterol acyltransferase; LDL, low-

density lipoprotein; LPL, lipoprotein

lipase; VLDL, very low-density

lipoprotein.