The LDLs (containing cholesteryl esters) are taken up by cells by a process
known as receptor-mediated endocytosis. The LDL receptor mediates this
endocytosis and is important to cholesterol metabolism. LDLs bind to these
receptors, which recognize apoprotein B-100. After LDL binding to the LDL
receptor, the ligand-receptor complexes cluster on the plasma membrane in
coated pits, which then invaginate forming coated vesicles. These coated vesi-
cles are internalized and clathrin, the protein composing the lattice in mem-
brane coated pits, is removed. These vesicles are now called endosomes and
these endosomes fuse with the lysosome. The LDL receptor-containing mem-
brane buds off and is recycled to the plasma membrane. Fusion of the lyso-
some and endosome releases lysosomal proteases that degrade the apoproteins
into amino acids. Lysosomal enzymes also hydrolyze the cholesteryl esters to
free cholesterol and fatty acids. The free cholesterol is released into the cell’s
cytoplasm, and this free cholesterol is then available to be used by the cell.
Excess cholesterol is reesterified by acyl-CoA: cholesterol acyltransferase
(ACAT), which uses fatty acyl-CoA as the source of activated fatty acid. Free
cholesterol affects cholesterol metabolism by inhibiting cholesterol biosynthe-
sis. Cholesterol inhibits the enzyme P-hydroxy-P-methylglutaryl-CoA reduc-
tase (HMG-CoA reductase), which catalyzes an early rate-limiting step in
cholesterol biosynthesis. HMG-CoA reductase is the target of the statin drugs
in wide use for treating patients with elevated cholesterol levels. In addition,
free cholesterol inhibits the synthesis of the LDL receptor, thus limiting the
amount of LDLs that are taken up by the cell.
Hyperlipidemia is defined as elevated lipoprotein levels in the plasma,
which may be primary or secondary. Several different types of hereditary
hyperlipidemias have been defined.
Type I—A relatively rare inherited deficiency of either lipoprotein
lipase activity or the lipoprotein lipase-activating protein apo C-II. This
results in the inability to effectively remove chylomicrons and VLDL
triglycerides from the blood.
Type II—Includes familial hypercholesterolemia described in detail
Type III—Associated with abnormalities of apolipoprotein E (apo E)
and defective conversion and removal of VLDL from the plasma.
Type IV—A common disorder characterized by variable elevations of
plasma triglycerides contained predominantly in VLDL. This leads to a
possible predisposition to atherosclerosis and often has a familial
Type V—An uncommon disorder, sometimes familial, associated with
defective clearance of exogenous and endogenous triglycerides and the
risk of life-threatening pancreatitis.