Blood - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 11

1.3.4.1 Cholesterol

Cholesterol (Cs, Vol. 1 - Chap. 7. Plasma Membrane), from extracellular sources
as well as de novo synthesis 12 is transported in blood mainly as cholesteryl esters
associated with lipoproteins (blood Cs concentration

< 2 . 2 g/l at 20 years old and

< 6 g/l at 60 years old).

Dietary cholesteryl esters are carried from the small intestine to the liver by
chylomicrons. 13 A part is excreted in biliary ducts as free cholesterol or bile
acids (partial cyclic travel) and another part is conveyed in blood within LDL 14 or
VLDL particles. 15 LDL particles link to specific plasmalemmal receptors. They are
incorporated in vesicles, which fuse with lysosomes for degradation. 16 Endocytosis
via LDLR requires ApoB100 constituent. Agent ApoE synthesized in various organs
and found in high concentration in interstitial fluid, is a ligand for LDL receptors
that participate in cholesterol redistribution [ 7 ]. 17

2 .

1.3.4.2 High-Density Lipoproteins

High-density lipoproteins (5-17 nm, 1.06-1.21 g/ml) are synthesized in the liver 18
and small intestine. 19

They extract cholesterol from cell membranes with ApoA1

and ApoA2 [ 11 ]. 20

12 Endogenous cholesterol is synthesized in the liver and carried to tissues by VLDLs.
13 Cholesterol esters and triglycerides packed into chylomicrons in the gut are conveyed in lymph
and then in blood. Chylomicron is removed from blood by the liver.
14 Endogenous and exogenous cholesterol that exceeds hepatic needs is carried in the blood
circulation by LDL particles.
15 The liver synthesizes VLDL particles. These particles are plasma carriers of cholesterol after
conversion of VLDLs to LDLs by lipoprotein lipases, in particular in endothelial cells.
16 The sequential steps of the cellular LDLR destiny include: (1) LDL receptor binding; (2) coated
pit formation; (3) endocytosis; (4) lysosomal hydrolysis; and (5) metabolism via a passage into the
endoplasmic reticulum and Golgi body to come back to the plasma membrane [ 6 ].
17 ApoE mutants that cannot bind LDL receptors is associated with familial type 3 hyperlipopro-
teinemia, a genetic disorder with elevated plasma cholesterol levels and coronary artery disease.
18 Synthesis of new high-density lipoproteins begins with the secretion of apolipoprotein-A1
from the liver. Apolipoprotein-A1 can bind to the ATP-binding cassette transporter-A1 (ABCa1)
on macrophages in the subendothelial space. Agent ApoA1 promotes efflux of cholesterol and
phospholipids from macrophages that form nascent HDLs [ 8 ]. These particles can then be modified
by the lecithin-cholesterol acyltransferase into larger, less dense HDL2 and smaller, denser HDL3.
Both HDL2 and HDL3 can receive additional cholesterol from macrophages before entering into
blood circulation.
19 Intestine is an important source of HDL particles. The ABCA1 gene in the intestine plays a key
role in the production of high-density lipoproteins. Concentration of HDLs in mice with deleted
ABCA1 gene specifically in the intestine are 30% lower than in normal mice [ 9 ]. When the ABCA1
gene is deleted in both liver and intestine, HDL concentration is lowered by more than 90%.
20 Membrane-associated cholesterol is esterified by HDL-associated lecithin cholesterol acyltrans-
ferase (LCAT). Cholesterol efflux especially requires ApoA1-containing HDLs [ 10 ].