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chapter 19
Lipids II: Phospholipids, Glycosphingolipids, and Cholesterol
C YTO SO L
Acetyl-C oA + Acetyl-CoA
I '- CoASH
A cetoacetyl-C oA
A c e t y l - C o A - J Q _CoA
C oA SH
sy th eta se
iHMG-CoAl
2NADPH + a H 'k
„ .
^ HM G-CoA
2NADP+- y
red u ctase
Isopentenyl-tR N A *
M evalonate
»
;
Isoprenyl p yrophosphates
1
D0liCh0'
Famesyl
Pyr°Ph0SPhate
SSffiSSf*
r
l
C holesterol
tran sferase
' F arnesylated
proteins
- C o Q
►Heme A
M ITOCHONDRIA
Acetyl-CoA + Acetyl-CoA
C oA SH
A c eto a cety l-C o A -
D ea cy la se
A cetyl-C oA - J Hm q _CoA
C oA SH
C oA SH
^
S y 1 h e t a S 8
A cetoacetate*
IHMG-CoAl
O xidation
Leucine
HMG-CoA
lyase
Main route of
k eto g en esis
Acetyl-C oA
-A cetoacetate*
NADH + H
ß-Hydroxybutyrate
dehydrogenase ^ N A D +
d(-)-
p-Hydroxybutyrate *
*
'C ? ‘
A ceton e
F I G U R E 19-1«
Mitochondrial and cytosolic biosynthesis and utilization of HMG-CoA in the liver. The molecules indicated by an
asterisk are the ketone bodies. Acetoacetate and /i-hydroxybutyrate (after conversion to acetoacetate) are metabolized
in extrahepatic tissues. Acetone is excreted in the lungs. Note the cytosolic multifunctional isoprenoid pathway for
cholesterol biosynthesis. The double arrow indicates a multistep pathway.
mitochondrial and concerned with formation of ketone
bodies, the other extramitochondrial and involved with
synthesis of isoprenoid units.
Conversion of HMG-CoA to Mevalonate
This two-step reduction reaction is the rate-limiting
step in cholesterogenesis. Cytosolic HMG-CoA is re-
duced by NADPH to mevalonate by HMG-CoA reduc-
tase through the production of an enzyme-bound aldehyde
intermediate:
o
c h 3
o
Il
I
II
O — c — C H 2— C — C H 2C — SC o A + 2NADPH + 2H +
I
OH
HM G— C oA
H M G -CoA reductase
O
C H 3
Il
I
o — C — C H 2— C — C H 2— C H 2OH + C o A SH + 2NADP +
I
OH
Mevalonate
HMG-CoA reductase is an integral protein of the endo-
plasmic reticulum and the primary site of regulation of
synthesis of cholesterol and nonsterol isoprenoid deriva-
tives. Its activity has a well-defined diurnal rhythm in rats
and mice, coinciding with that of the enzyme’s synthe-
sis and of the mRNA concentration. Activity is highest at
about the middle of the dark period and lowest at about
the middle of the light period. Its mechanism may be re-
lated to food consumption. Rats are nocturnal animals and
consume food in the dark; the increased bile production
and excretion depletes liver cholesterol and may stimu-
late the increased synthesis of HMG-CoA reductase as a
compensatory mechanism.
HMG-CoA
reductase
is
regulated
via
synthesis-
degradation
and
phosphorylation-dephosphorylation.
Phosphorylation decreases activity, whereas déphospho-
rylation increases it (Figure 19-11). The reductase kinase
phosphorylation
is
not
cAMP-dependent.
However,
cAMP dependence arises by way of activation of a
protein kinase, which phosphorylâtes a protein inhibitor
of phosphatase. The two phosphatases are identical. Thus,
increase in cAMP concentration inhibits phosphatase
activity, resulting in marked decrease in HMG-CoA
reductase activity. Elevation of the plasma glucagon level
(e.g., during fasting) activates cAMP production and
reduces cholesterol production. Activity is also inhibited
by oxygenated sterols (e.g., 27-hydroxy cholesterol) but
