SECTION 19.3
Cholesterol
415
eggs and meat. Plants, yeasts, and fungi contain sterols
that are structurally similar to cholesterol—sitosterols and
ergosterols—but are poorly absorbed by the human intesti-
nal tract. A rare inherited autosomal sterol storage disor-
der (
sitosterolemia)
is due to defects in the ATP-binding
cassette-family of transporters that mediate cholesterol
efflux. Treatment consists of diets low in plant sterol con-
tent and with cholestyramine to enhance sterol excretion
(Chapter 20). In intestinal mucosal cells, most of the ab-
sorbed cholesterol is esterified with fatty acids and incor-
porated into chylomicrons that enter the blood through
the lymph. After chylomicrons unload most of their tria-
cylglycerol content at the peripheral tissues, chylomicron
remnants are rapidly taken up by the liver (Chapter 20).
The routing of nearly all of the cholesterol derived from
dietary sources to the liver facilitates the balance of the
steroid content in the organism, since the liver is the prin-
cipal site of cholesterol production. Although the intestinal
tract, adrenal cortex, testes, skin, and other tissues can also
synthesize cholesterol, their contribution is a minor one.
Cholesterol biosynthesis proceeds via the isoprenoids
in a multistep pathway. The end product, cholesterol,
and the intermediates of the pathway participate in di-
verse cellular functions. The isoprenoid units give rise to
dolichol, CoQ, heme A, isopentenyl-tRNA, famesylated
proteins, and vitamin D (in the presence of sunlight and
7-dehydrocholesterol). Dolichol is used in the synthesis of
glycoproteins, CoQ in the mitochondrial electron transport
chain, famesylation and geranylgeranylation by posttrans-
lational lipid modification that is required for membrane
association and function of proteins such as p
2 1
ras and
G-protein subunits.
Cholesterol has several functions including involvement
in membrane structure, by modulation of membrane fluid-
ity and permeability, serving as a precursor for steroid hor-
mone and bile acid synthesis, in the covalent modification
of proteins, and formation of the central nervous system
in embryonic development. The latter role of cholesterol
was discovered through mutations and pharmacological
agents that block cholesterol biosynthesis that occurs in
six steps:
1. Conversion of acetyl-CoA to
3-hydroxy-3-methylglutaryl coenzyme-A
(HMG-CoA);
2. Conversion of HMG-CoA to mevalonate, the
rate-limiting step in cholesterol biosynthesis;
3. Conversion of mevalonate to isoprenyl
pyrophosphates with loss of CO
2
;
4. Conversion of isoprenyl pyrophosphates to squalene;
5. Conversion of squalene to lanosterol; and
6
. Conversion of lanosterol to cholesterol.
The biosynthetic reactions involve a series of conden-
sation processes and are distributed between cytosol and
microsomes. All of the carbons of cholesterol are derived
from acetyl-CoA, 15 from the “methyl” and 12 from the
“carboxyl” carbon atoms. Acetyl-CoA is derived from mi-
tochondrial oxidation of metabolic fuels (e.g., fatty acids)
and transported to cytosol as citrate (Chapter 18) or by
activation of acetate (e.g., derived from ethanol oxidation)
by cytosolic acetyl-CoA synthase (Chapter 18). All of the
reducing equivalents are provided by NADPH.
Conversion of Acetyl-CoA to HMG-CoA
In the cytosol, three molecules of acetyl-CoA are con-
densed to HMG-CoA through successive action of thio-
lase and HMG-CoA synthase, respectively (Figure 19-9).
HMG-CoA synthase is under transcriptional regulation by
the sterol end products.
HMG-CoA is also synthesized in mitochondria by the
same sequence of reactions but yields the ketone bod-
ies acetoacetate,
D ( —
)-/l-hydroxybutyrate, and acetone
(Figure 19-10). Mitochondrial HMG-CoA also arises
from oxidation of leucine (Chapter 17), which is keto-
genic. Although HMG-CoA derived from leucine is not
utilized in mevalonate synthesis, the carbon of leucine
can be incorporated into cholesterol by way of acetyl-
CoA. Thus, two distinct pools of HMG-CoA exist: one
O
O
II
II
H3C —
c—
S C oA
+
CH3—
-c—
SC oA
A cetyl-C oA
T h iolase
C oA SH
o
o
II
II
H3c—
C — CH —
c—
SC oA
A cetoacetyl-C oA
O
II
^ - C H 3— C — SC oA
HM G-CoA sy n th a se
CoASH
9H,
O
_
I
II
O O C — CH — C — CH —
c—
SC oA
OH
3-H ydroxy-3-m ethylglutaryl-CoA
(HM G-CoA)
F IG U R E 1 9 -9
Biosynthesis of HMG-CoA.
