UNIT III:
Lipid Metabolism
Cholesterol and Steroid
Metabolism
E. Metabolism of HDL
 HDL comprise a heterogeneous family of lipoproteins with a
complex metabolism that is not yet completely understood.
 HDL particles are formed in blood by the addition of lipid to
apo A-1, an apolipoprotein made by the liver and intestine and
secreted into blood.
 Apo A-1 accounts for about 70% of the apoproteins in HDL.
 HDL perform a number of important functions, including the
following:
1.
HDL is a reservoir of apolipoproteins: HDL particles serve as a
circulating reservoir of:
 apo C-II (the apolipoprotein that is transferred to VLDL and
chylomicrons, and is an activator of lipoprotein lipase),
 and apo E (the apolipoprotein required for the receptor-mediated
endocytosis of IDLs and chylomicron remnants).
E. Metabolism of HDL
2.
HDL uptake of unesterified cholesterol:
 Nascent HDL are disk-shaped particles containing primarily
phospholipid (largely phosphatidylcholine) and apolipoproteins A,
C, and E.
 They are rapidly converted to spherical particles as they
accumulate cholesterol (Figure 18.23).
Note:
 HDL particles are excellent acceptors of unesterified cholesterol
(both from other lipoproteins particles and from cell membranes) as
a result of their high concentration of phospholipids, which are
important solubilizers of cholesterol.
E. Metabolism of HDL
3. Esterification of cholesterol: When cholesterol is taken up by
HDL, it is immediately esterified by the plasma enzyme
phosphatidylcholine:cholesterol acyltransferase (PCAT, also
known as LCAT, in which “L” stands for lecithin).




This enzyme is synthesized by the liver. PCAT binds to nascent HDL,
and is activated by apo A-I.
PCAT transfers the fatty acid from carbon 2 of phosphatidylcholine
to cholesterol.
This produces a hydrophobic cholesteryl ester, which is sequestered
in the core of the HDL, and lysophosphatidylcholine, which binds to
albumin.
As the nascent HDL accumulates cholesteryl esters, it first becomes a
relatively cholesteryl ester–poor HDL3 and, eventually, a cholesteryl
ester–rich HDL2 particle that carries these esters to the liver.
Figure 18.23 Metabolism of HDL. PC = phosphatidylcholine; lyso-PC =
lysophosphatidylcholine. PCAT = Phosphatidylcholine cholesterol
transferase. CETP = cholesteryl ester transfer protein. ABCA1 = transport
protein. [Note: For convenience the size of VLDLs are shown smaller than
HDL, whereas VLDLs are larger than HDL.]
5
E. Metabolism of HDL
4. Reverse cholesterol transport: The selective transfer of
cholesterol from peripheral cells to HDL, and from HDL to the liver
for bile acid synthesis or disposal via the bile, and to steroidogenic
cells for hormone synthesis, is a key component of cholesterol
homeostasis.
 This is, in part, the basis for the inverse relationship seen between
plasma HDL concentration and atherosclerosis, and for HDL's
designation as the “good” cholesterol carrier.
 Reverse cholesterol transport involves efflux of cholesterol from
peripheral cells to HDL, esterification of cholesterol by PCAT, binding
of the cholesteryl ester–rich HDL (HDL2) to liver and steroidogenic
cells, the selective transfer of the cholesteryl esters into these cells,
and the release of lipid-depleted HDL (HDL3).
E. Metabolism of HDL
 The efflux of cholesterol from peripheral cells is mediated, at least in
part, by the transport protein, ABCA1.
Note:
 Tangier disease is a very rare deficiency of ABCA1, and is
characterized by the virtual absence of HDL particles due to
degradation of lipid-poor apo A-1.
 The uptake of cholesteryl esters by the liver is mediated by a cellsurface receptor, SR-B1 (scavenger receptor class B type 1) that binds
HDL (see p, 234 for SR-A).
 It is not yet clear as to whether the HDL particle itself is taken up, the
cholesteryl esters extracted, and the lipid-poor HDL released back
into the blood, or if there is selective uptake of the cholesteryl ester
alone.
Figure 18.23 Metabolism of HDL. PC = phosphatidylcholine; lyso-PC =
lysophosphatidylcholine. PCAT = Phosphatidylcholine cholesterol
transferase. CETP = cholesteryl ester transfer protein. ABCA1 = transport
protein. [Note: For convenience the size of VLDLs are shown smaller than
HDL, whereas VLDLs are larger than HDL.
8
E. Metabolism of HDL
Note:
 Hepatic lipase, with its ability to degrade both TAG and
phospholipids, participates in the conversion of HDL2 to
HDL3
 ABCA1 is an ATP-binding cassette (ABC) protein.
 ABC proteins use energy from ATP hydrolysis to transport
materials, including lipids, in and out of cells and across
intracellular compartments.
 In addition to Tangier disease, defects in specific ABC
proteins result in X-linked adrenoleukodystrophy,
respiratory distress syndrome due to decreased surfactant
secretion, and cystic fibrosis.
F. Role of lipoprotein (a) in heart disease
 Lipoprotein (a), or Lp(a), is a particle that, when present
in large quantities in the plasma, is associated with an
increased risk of coronary heart disease.
 Lp(a) is nearly identical in structure to an LDL particle.
 Its distinguishing feature is the presence of an additional
apolipoprotein molecule, apo(a), that is covalently linked
at a single site to apo B-100.
 Circulating levels of Lp(a) are determined primarily by
genetics.
F. Role of lipoprotein (a) in heart disease
 However, factors such as diet may play some role, as
trans fatty acids have been shown to increase Lp(a), and
estrogen decreases both LDL and Lp(a).
Note:
 Apo(a) is structurally homologous to plasminogen—the
precursor of a blood protease whose target is fibrin, the
main protein component of blood clots.
 It is hypothesized that elevated Lp(a) slows the
breakdown of blood clots that trigger heart attacks
because it competes with plasminogen for binding to
fibrin.
7- Steroid Hormones
 Cholesterol is the precursor of all classes of steroid hormones:
glucocorticoids (for example, cortisol), mineralocorticoids (for
example, aldosterone), and sex hormones—androgens,
estrogens, and progestins (Figure 18.24).
Note:
Glucocorticoids and mineralocorticoids are collectively called
corticosteroids.
 Synthesis and secretion occur in the adrenal cortex (cortisol,
aldosterone, and androgens), ovaries and placenta (estrogens
and progestins), and testes (testosterone).
 Steroid hormones are transported by the blood from their sites
of synthesis to their target organs.
Figure 18.24 Key
steroid hormones.
7- Steroid Hormones
 Because of their hydrophobicity, they must be complexed
with a plasma protein.
 Plasma albumin can act as a nonspecific carrier, and does
carry aldosterone.
 However, specific steroid-carrier plasma proteins bind the
steroid hormones more tightly than does albumin, for
example,
 corticosteroid-binding globulin (transcortin) is responsible for
transporting cortisol,
 and sex hormone–binding protein transports sex steroids.
A. Synthesis of steroid hormones
 Synthesis involves shortening the hydrocarbon chain of
cholesterol, and hydroxylation of the steroid nucleus.
 The initial and rate-limiting reaction converts cholesterol to the
21-carbon pregnenolone
 It is catalyzed by the cholesterol side-chain cleavage enzyme
complex (desmolase)—a CYP mixed function oxidase of the
inner mitochondrial membrane.
 NADPH and molecular oxygen are required for the reaction.
 The cholesterol substrate can be newly synthesized, taken up
from lipoproteins, or released from cholesteryl esters stored in
the cytosol of steroidogenic tissues.
 An important control point is the movement of cholesterol
into mitochondria. This process is mediated by StAR
(steroidogenic acute regulatory protein).
A. Synthesis of steroid hormones
Note:
 Steroid hormone synthesis consumes little cholesterol as
compared with that required for bile acid synthesis.
 Pregnenolone is the parent compound for all steroid
hormones
 Pregnenolone is oxidized and then isomerized to
progesterone, a progestin, which is further modified to
the other steroid hormones by hydroxylation reactions
that occur in the ER and mitochondria.
 Like desmolase, the enzymes are CYP proteins.
17
B. Secretion of steroid hormones from
adrenal cortex & gonads
 Steroid hormones are secreted on demand from adrenal
cortex in response to hormonal signals.
1. Cortisol
2. Aldosterone
3. Androgens
 The testes and ovaries synthesize hormones necessary for
physical development and reproduction.
 The testes to produce testosterone and the ovaries to produce
estrogens and progesterone
E. Further metabolism of steroid
hormones
 Steroid hormones are generally converted into inactive
metabolic excretion products in the liver.
 Reactions include reduction of unsaturated bonds and the
introduction of additional hydroxyl groups.
 The resulting structures are made more soluble by conjugation
with glucuronic acid or sulfate
 Approximately 20–30% of these metabolites are secreted into
the bile and then excreted in the feces, whereas the remainder
are released into the blood and filtered from the plasma in the
kidney, passing into the urine.
 These conjugated metabolites are fairly water-soluble and do
not need protein carriers.
8- Chapter Summary
 Cholesterol is a hydrophobic compound, with a single hydroxyl
group—located at carbon 3 of the A ring—to which a fatty acid
can be attached, producing an even more hydrophobic
cholesteryl ester.
 Cholesterol is synthesized by virtually all human tissues,
although primarily by liver, intestine, adrenal cortex, and
reproductive tissues (Figure 18.29).
 All the carbon atoms in cholesterol are provided by acetate, and
NADPH provides the reducing equivalents.
 The pathway is driven by hydrolysis of the high-energy thioester
bond of acetyl coenzyme A (CoA) and the terminal phosphate
bond of ATP.
8- Chapter Summary
 Cholesterol is synthesized in the cytoplasm.
 The rate-limiting and regulated step in cholesterol synthesis
is catalyzed by the endoplasmic reticulum–-membrane
protein, hydroxymethylglutaryl (HMG) CoA reductase,
which produces mevalonic acid from HMG CoA.
 The enzyme is regulated by a number of mechanisms:
1.
Expression of the HMG CoA reductase gene is activated when
cholesterol levels are low, resulting in increased enzyme and,
therefore, more cholesterol synthesis.
8- Chapter Summary
2. HMG CoA reductase activity is controlled covalently through the
actions of an adenosine monophosphate (AMP)–activated
protein kinase (AMPK, which phosphorylates and inactivates
HMG CoA reductase) and an insulin-activated protein
phosphatase (which activates HMG CoA reductase).
3. Statins are competitive inhibitors of HMG CoA reductase. These
drugs are used to decrease plasma cholesterol in patients with
hypercholesterolemia. The ring structure of cholesterol can not
be degraded in humans.
8- Chapter Summary
 Cholesterol can be eliminated from the body either by
conversion to bile salts or by secretion into the bile.
 Intestinal bacteria can reduce cholesterol to coprostanol and
cholestanol, which together with cholesterol make up the bulk
of neutral fecal sterols.
 Bile salts and phosphatidylcholine are quantitatively the most
important organic components of bile.
 Bile salts are conjugated bile acids produced by the liver and
stored in the gallbladder.
 The primary bile acids, cholic or chenodeoxycholic acids, are
amphipathic, and can serve as emulsifying agents.
8- Chapter Summary
 The rate-limiting step in bile acid synthesis is catalyzed by
cholesterol-7-α-hydroxylase, which is activated by cholesterol
and inhibited by bile acids.
 Before the bile acids leave the liver, they are conjugated to a
molecule of either glycine or taurine, producing the primary
bile salts: glycocholic or taurocholic acid, and
glycochenodeoxycholic or taurochenodeoxycholic acid.
 Bile salts are more amphipathic than bile acids and, therefore,
are more effective emulsifiers.
 In the intestine, bacteria can remove the glycine and taurine,
and can remove a hydroxyl group from the steroid nucleus,
producing the secondary bile acids—deoxycholic and
lithocholic acids.
8- Chapter Summary
 Bile is secreted into the intestine, and more than 95% of the
bile acids and salts are efficiently reabsorbed.
 They are actively transported from the intestinal mucosal cells
into the portal blood, where they are carried by albumin back
to the liver (enterohepatic circulation).
 In the liver, the primary and secondary bile acids are
reconverted to bile salts, and secreted into the bile.
 If more cholesterol enters the bile than can be solubilized by
the available bile salts and phosphatidylcholine, cholesterol
gallstone disease (cholelithiasis) can occur.
8- Chapter Summary
 The plasma lipoproteins include chylomicrons, very-lowdensity lipoproteins (VLDL), low-density lipoproteins (LDL),
and high-density lipoproteins (HDL).
 They function to keep lipids (primarily triacylglycerol and
cholesteryl esters) soluble as they transport them between
tissues.
 Lipoproteins are composed of a neutral lipid core (containing
triacylglycerol, cholesteryl esters, or both) surrounded by a
shell of amphipathic apolipoproteins, phospholipid, and
nonesterified cholesterol.
 Chylomicrons are assembled in intestinal mucosal cells from
dietary lipids (primarily, triacylglycerol) plus additional lipids
synthesized in these cells.
8- Chapter Summary
 Each nascent chylomicron particle has one molecule of
apolipoprotein (apo) B-48.
 They are released from the cells into the lymphatic system and
travel to the blood, where they receive apo C-II and apo E from
HDLs, thus making the chylomicrons functional.
 Apo C-II activates lipoprotein lipase, which degrades the
chylomicron's triacylglycerol to fatty acids and glycerol.
 The fatty acids that are released are stored (in the adipose) or
used for energy (by the muscle).
 The glycerol is metabolized by the liver.
 Patients with a deficiency of lipoprotein lipase or apo C-II show
a dramatic accumulation of chylomicrons in the plasma (Type I
hyperlipoproteinemia, familial lipoprotein lipase deficiency, or
hypertriacylglycerolemia).
8- Chapter Summary
 After most of the triacylglycerol is removed, apo C-II is
returned to the HDL, and the chylomicron remnant—carrying
most of the dietary cholesterol—binds to a receptor on the
liver that recognizes apo E.
 The particle is endocytosed and its contents degraded by
lysosomal enzymes.
 Nascent VLDL are produced in the liver, and are composed
predominantly of triacylglycerol.
 They contain a single molecule of apo B-100. Like nascent
chylomicrons, VLDL receive apo C-II and apo E from HDL in the
plasma.
 The function of VLDL is to carry triacylglycerol from the liver to
the peripheral tissues where lipoprotein lipase degrades the
lipid. As triacylglycerol is removed from the VLDL, the particle
receives cholesteryl esters from HDL.
8- Chapter Summary
 This process is accomplished by cholesteryl ester transfer
protein.
 Eventually, VLDL in the plasma is converted to LDL—a much
smaller, denser particle.
 Apo C-II and apo E are returned to HDL, but the LDL retains
apo B-100, which is recognized by receptors on peripheral
tissues and the liver.
 LDL undergo receptor-mediated endocytosis, and their
contents are degraded in the lysosomes.
 A deficiency of functional LDL receptors causes Type II
hyperlipidemia (familial hypercholesterolemia).
 The endocytosed cholesterol inhibits HMG CoA reductase and
decreases synthesis of LDL receptors.
8- Chapter Summary
 Some of it can also be esterified by acyl CoA:cholesterol
acyltransferase and stored.
 HDL are created by lipidation of apo A-1 synthesized in the liver
and intestine.
 They have a number of functions, including:
1.
serving as a circulating reservoir of apo C-II and apo E for
chylomicrons and VLDL;
2. removing unesterified cholesterol from cell surfaces and other
lipoproteins and esterifying it using
phosphatidylcholine:cholesterol acyl transferase, a liversynthesized plasma enzyme that is activated by apo A-1; and
3. delivering these cholesteryl esters to the liver (“reverse
cholesterol transport”).
8- Chapter Summary
 Cholesterol is the precursor of all classes of steroid hormones
(glucocorticoids, mineralocorticoids, and sex hormones—
androgens, estrogens, and progestins).