424
chapter 19
Lipids II: Phospholipids, Glycosphingolipids, and Cholesterol
7a-hydroxylase; the reaction requires NADPH, O
2
, cy-
tochrome P-450, and NADPH: cytochrome P-450 re-
ductase.
Reactions that follow are oxidation of the
3/1-hydroxyl group to a 3-keto group, isomerization of
the A
5
double bond to the A
4
-position, conversion of
the 3-keto group to a 3a-hydroxyl group, reduction
of the A
4
double bond, 12a-hydroxylation in the case
of cholic acid synthesis, and oxidation of the side chain.
12a-Hydroxylase, like 7a-hydroxylase, is associated with
microsomes and requires NADPH, molecular oxygen, and
cytochrome P-450. Unlike 7a-hydroxylase, its activity
does not exhibit diurnal variation. Its activity determines
the amount of cholic acid synthesized. Side chain oxi-
dation starts with 27-hydroxylation and is followed by
oxidative steps similar to those of /
1
-oxidation of fatty
acids (Chapter 18). The 27-hydroxylation catalyzed by a
mixed-function hydroxylase probably occurs in mitochon-
dria and requires NADPH, O
2
, and cytochrome P-450. Bile
acid deficiency in cerebrotendinous xanthomatosis (see
above) is due to a deficiency of 27-hydroxylase. Since
the substrates for bile acid formation are water insolu-
ble, they require sterol carrier proteins for synthesis and
metabolism.
Bile acids are conjugated with glycine or taurine
(Figure 19-18) before being secreted into bile, where the
ratio of glycine- to taurine-conjugated acids is about 3:1.
Sulfate esters of bile acids are also formed to a small ex-
tent. At the alkaline pH of bile and in the presence of
alkaline cations (Na+, K+), the acids and their conjugates
are present as salts (ionized forms), although the terms
bile
acids
and
bile salts
are used interchangeably.
Regulation of Bile Acid Synthesis
Regulation of bile acid formation from cholesterol oc-
curs at the 7a-hydroxylation step and is mediated by the
concentration of bile acids in the enterohepatic circula-
tion. 7a-Hydroxylase is modulated by a phosphorylation-
dephosphorylation cascade similar to that of HMG-CoA
reductase (Figure 19-11) except that the phosphorylated
form of 7a-hydroxylase is more active.
As noted earlier, the major rate-limiting step of choles-
terol biosynthesis is reduced synthesis of HMG-CoA.
7a-hydroxycholesterol, the first intermediate of bile acid
formation, inhibits HMG-CoA reductase. The activities
of 7a-cholesterol hydroxylase and HMG-CoA reductase
undergo parallel changes under the influence of bile acid
levels. In the rat, they show similar patterns of diurnal
variation, with highest activities during the dark period.
Bile acids and intermediates do not appear to function
as allosteric modifiers. In the intestines, bile acids may
regulate cholesterol biosynthesis, in addition to their role
in cholesterol absorption. In humans, the presence of ex-
cess cholesterol does not increase bile acid production pro-
portionally, although it suppresses endogenous cholesterol
synthesis and increases excretion of fecal neutral steroids.
Hepatic
bile
acid
synthesis
amounts
to
about
0.8-1 g/day. When loss of bile occurs owing to drainage
O
O
R — C — SC oA
Cholyl-CoA
HQ,S— CH2—CHj—NH2—^ /
'
Taurine
y
CoASH «------
y
R — C — SC oA
C henodeoxycholyl-C oA
NH— CH — COOH H 0
3
S — C H — CH— NH2— .
/
G lycine
CoASH
Taurine
V
C oASH --------
7
O
/
N H — C H — COOt
G lycine
CoASH
R— C — N— CH — C H — S 0 3H
H
Taurocholic acid
R — C — N— CH — COOH
H
G lycocholic acid
R— C— N— CH — CH— S03H
H
Taurochenodeoxycholic acid
R— C — N— CH — COOH
H
!
G lycochenodeoxycholic acid
FIGURE 19-18
Conjugation of bile acids with taurine and glycine.
