section 19.3
Cholesterol
421
and hydride shifts along the squalene chain. In both stages,
the reactants are bound to supernatant protein factor (SPF),
a cytosolic carrier that promotes conversion of squalene
to lanosterol.
Conversion of Lanosterol to Cholesterol
Transformation of lanosterol to cholesterol (Figure 19-16)
is a complex, multistep process catalyzed by enzymes
of the endoplasmic reticulum (microsomes). A cytosolic
sterol carrier protein is also required and presumably func-
tions as a carrier of steroid intermediates from one catalytic
site to the next but may also affect activity of the enzymes.
The reactions consist of removal of the three methyl groups
attached to C
4
and C
1 4
, migration of the double bond from
the 8,9- to the 5,6-position, and saturation of the double
bond in the side chain. Conversion of lanosterol to choles-
terol occurs principally via 7-dehydrocholesterol and to a
minor extent via desmosterol.
The importance of cholesterol biosynthesis in em-
bryonic development and formation of the central ner-
vous system is reflected in patients with disorders in
the pathway for the conversion of lanosterol to choles-
terol. Three enzyme deficiencies have been identified
(Figure 19-16):
1. 3/i-Hydroxysteroid-A24-reductase (also known as
sterol- A
2 4
-reductase);
2. 3/f-Hydroxysteroid-A
8
,A7-isomerase (commonly
known as sterol-A
8
-isomerase);
3. 3/UHydroxysteroid-A7-rcductase (also known as
7-dehydrocholesterol reductase).
Sterol-A8-isomerase deficiency, known as
Conradi-
Hiinermann syndrome
(CDPX2), is an X-linked dominant
disorder. Clinical manifestations of this disorder include
skeletal abnormalities, chondrodysplasia punctata, cran-
iofacial anomalies, cataracts, and skin abnormalities. The
7-dehydrocholesterol
reductase deficiency,
known
as
Smith-Lemli-Opitz syndrome (SLO)
is an autosomal
recessive disorder occurring in about
1
in
2 0 , 0 0 0
births.
Clinical manifestations of affected individuals include
craniofacial abnormalities, microcephaly, congenital heart
disease, malformation of the limbs, psychomotor retar-
dation, cerebral maldevelopment, and urogenital anoma-
lies. Measurement of 7-dehydrocholesterol in amniotic
fluid during second trimester or in neonatal blood spec-
imen has been useful in the identification of the disorder.
The sterol-A24-reductase deficiency causes a developmen-
tal phenotype similar to SLO syndrome and is associ-
ated with accumulation of desmosterol. The inability of
de novo
fetal synthesis of cholesterol combined with its
inadequate transport from the mother to the fetus appears
to be involved in the multiple abnormalities of morpho-
genesis. SLO infants treated with rich sources of dietary
cholesterol after birth have shown fewer growth abnor-
malities. However, it is not known whether long-term di-
etary cholesterol supplement can improve cognitive devel-
opment, particularly since cholesterol is not transported
across the blood-brain barrier.
An appreciation of the relationship between cellu-
lar cholesterol metabolism and a family of signaling
molecules that participate in embryonic development is
emerging. These signaling molecules are known as
hedge-
hog proteins
which were initially identified in
Drosophila.
The vertebrate counterparts of hedgehog proteins, partic-
ipate in embryonic processing, including the neural tube
and its derivatives, the axial skeleton, and the appendages.
The hedgehog protein is a self-splicing protein that under-
goes an autocatalytic proteolytic processing giving rise to
an N-terminal and a C-terminal product. In
Drosophila,
hedgehog protein cleavage occurs between Gly-257 and
Cys-258. Cholesterol is covalently attached to the carboxy
terminal end of the N-terminal cleavage product. Both
the autocatalytic proteolysis and intramolecular choles-
terol transferase activities are located in the C-terminal
portion of the hedgehog protein. The covalent modifica-
tion of the N-terminal segment of the hedgehog protein is
necessary for proper localization on the cell membrane at
target sites to initiate downstream events (e.g., transcrip-
tion of target genes). Thus, perturbations of cholesterol
biosynthesis due to mutations or pharmacological agents
can lead to defects in embryonic development.
Utilization of Cholesterol
Cholesterol
is
utilized
in
formation
of membranes
(Chapter 10), steroid hormones (Chapters 30, 32, and 34),
and bile acids. 7-Dehydrocholesterol is required for pro-
duction of vitamin D (Chapter 37). Under steady-state con-
ditions, the cholesterol content of the body is maintained
relatively constant by balancing synthesis and dietary in-
take with utilization. The major consumer of cholesterol
is formation of bile acids, of which about
0
.
8 - 1
g/day are
produced in the liver and lost in the feces. However, se-
cretion of bile acids by the liver is many times greater
(15-20 g/day) than the rate of synthesis because of their
enterohepatic circulation (Chapter 12). Cholesterol is also
secreted into bile, and some is lost in feces as choles-
terol and as coprostanol, a bacterial reduction product
(about 0.4-0.5 g/day). Conversion of cholesterol to steroid
hormones and of 7-dehydrocholesterol to vitamin D and
elimination of their inactive metabolites, are of minor sig-
nificance in the disposition of cholesterol, amounting to
approximately 50 mg/day. A small amount of cholesterol
