Introduction to Carbohydrates

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Transcript Introduction to Carbohydrates

UNIT III:
Lipid Metabolism
Cholesterol and Steroid
Metabolism
I. Overview
• Cholesterol, the characteristic steroid alcohol of animal
tissues, performs a number of essential functions in the
body.
• For example, cholesterol is a structural component of all cell
membranes, modulating their fluidity, and, in specialized
tissues, cholesterol is a precursor of bile acids, steroid
hormones, and vitamin D.
• It is therefore of critical importance that the cells of the body
be assured an appropriate supply of cholesterol.
• To meet this need, a complex series of transport,
biosynthetic, and regulatory mechanisms has evolved.
• The liver plays a central role in the regulation of the body's
cholesterol homeostasis.
• For example, cholesterol enters the liver's cholesterol
pool from a number of sources including dietary
cholesterol, as well as cholesterol synthesized de novo
by extrahepatic tissues and by the liver itself.
• Cholesterol is eliminated from the liver as unmodified
cholesterol in the bile, or it can be converted to bile salts
that are secreted into the intestinal lumen.
• It can also serve as a component of plasma lipoproteins
sent to the peripheral tissues.
• In humans, the balance between cholesterol influx and
efflux is not precise, resulting in a gradual deposition of
cholesterol in the tissues, particularly in the endothelial
linings of blood vessels.
• This is a potentially life-threatening occurrence when the
lipid deposition leads to plaque formation, causing the
narrowing of blood vessels (atherosclerosis) and
increased risk of coronary artery disease.
The major sources of liver cholesterol
and the routes by which
cholesterol leaves the liver
II. Structure of Cholesterol
• Cholesterol is a very hydrophobic
compound. It consists of four fused
hydrocarbon rings (A, B, C, and D,
called the “steroid nucleus”), and it has
an eight-carbon, branched hydrocarbon
chain attached to C-17 of the D ring.
• Ring A has a hydroxyl group at C-3, and
ring B has a double bond between C-5
and C-6 (Figure 18.2).
• Figure 18.2 Structure
of cholesterol and its
ester.
A. Sterols
•
•
•
Steroids with 8–10 carbon atoms in the side chain at C17 and a hydroxyl group at C-3 are classified as sterols.
Cholesterol is the major sterol in animal tissues.
[Note: Plant sterols, such as β-sitosterol are poorly
absorbed by humans. After entering the enterocytes,
they are actively transported back into the intestinal
lumen. Because some cholesterol is transported as
well, plant sterols appear to block the absorption of
dietary cholesterol. This has led to clinically useful
dietary treatment of hypercholesteremia. Daily ingestion
of plant steroid esters (in the form of commercially
available trans fatty acid–free margarine) is one of a
number of dietary strategies leading to the reduction of
plasma cholesterol levels]
B. Cholesteryl esters
• Most plasma cholesterol is in an esterified form (with a
fatty acid attached at C-3), which makes the structure
even more hydrophobic than free cholesterol.
• Cholesteryl esters are not found in membranes, and are
normally present only in low levels in most cells.
• Because of their hydrophobicity, cholesterol and its
esters must be transported in association with protein as
a component of a lipoprotein particle or be solubilized by
phospholipids and bile salts in the bile.
III. Synthesis of Cholesterol
• Cholesterol is synthesized by virtually all tissues in
humans, although liver, intestine, adrenal cortex, and
reproductive tissues, including ovaries, testes, and
placenta, make the largest contributions to the body's
cholesterol pool.
• As with fatty acids, all the carbon atoms in cholesterol
are provided by acetate, and NADPH provides the
reducing equivalents.
• The pathway is endergonic, being driven by hydrolysis of
the high-energy thioester bond of acetyl coenzyme A
(CoA) and the terminal phosphate bond of adenosine
triphosphate (ATP).
• Synthesis occurs in the cytoplasm, with
enzymes in both the cytosol and the membrane
of the endoplasmic reticulum.
• The pathway is responsive to changes in
cholesterol concentration, and regulatory
mechanisms exist to balance the rate of
cholesterol synthesis within the body against the
rate of cholesterol excretion.
• An imbalance in this regulation can lead to an
elevation in circulating levels of plasma
cholesterol, with the potential for coronary artery
disease.
A.
Synthesis of 3-hydroxy-3-methylglutaryl (HMG) CoA
•
The first two reactions in the cholesterol synthetic
pathway are similar to those in the pathway that
produces ketone bodies.
They result in the production of HMG CoA.
First, two acetyl CoA molecules condense to form
acetoacetyl CoA.
Next, a third molecule of acetyl CoA is added,
producing HMG CoA, a six-carbon compound.
[Note: Liver parenchymal cells contain two isoenzymes
of HMG CoA synthase. The cytosolic enzyme
participates in cholesterol synthesis, whereas the
mitochondrial enzyme functions in the pathway for
ketone body synthesis.]
•
•
•
•
• Figure 18.3
Synthesis of HMG
CoA.
B. Synthesis of mevalonic acid (mevalonate)
• The next step, the reduction of HMG CoA to
mevalonic acid, is catalyzed by HMG CoA
reductase, and is the rate-limiting and key
regulated step in cholesterol synthesis.
• It occurs in the cytosol, uses two molecules of
NADPH as the reducing agent, and releases
CoA, making the reaction irreversible.
• [Note: HMG CoA reductase is an intrinsic
membrane protein of the endoplasmic reticulum
(ER), with the enzyme's catalytic domain
projecting into the cytosol.
C. Synthesis of cholesterol
• The reactions and enzymes involved in the
synthesis of cholesterol from mevalonate
are illustrated in Figure 18.5.
• [Note: The numbers shown in brackets
below correspond to numbered reactions
shown in this figure.]
[1] Mevalonic acid is converted to 5pyrophosphomevalonate in two steps, each of
which transfers a phosphate group from ATP.
[2] A five-carbon isoprene unit—isopentenyl
pyrophosphate (IPP)—is formed by the
decarboxylation of 5-pyrophosphomevalonate.
The reaction requires ATP.
• [Note: IPP is the precursor of a family of
molecules with diverse functions, the
isoprenoids. Cholesterol is a sterol isoprenoid.
Nonsterol isoprenoids include dolichol and
ubiquinone.]
• Figure 18.4
Synthesis of
mevalonic acid.
[3] IPP is isomerized to 3,3-dimethylallyl pyrophosphate
(DPP).
[4] IPP and DPP condense to form ten-carbon geranyl
pyrophosphate (GPP).
[5] A second molecule of IPP then condenses with GPP to
form 15-carbon farnesyl pyrophosphate (FPP).
• [Note: Covalent attachment of farnesyl to proteins, a
process known as “prenylation,” is one mechanism for
anchoring proteins to plasma membranes.]
[6] Two molecules of FPP combine, releasing
pyrophosphate, and are reduced, forming the 30-carbon
compound squalene.
• [Note: Squalene is formed from six isoprenoid units.
Because three ATP are hydrolyzed per mevalonic acid
residue converted to IPP, a total of 18 ATP are required
to make the polyisoprenoid squalene.]
[7] Squalene is converted to the sterol lanosterol by a
sequence of reactions that use molecular oxygen and
NADPH. The hydroxylation of squalene triggers the
cyclization of the structure to lanosterol.
[8] The conversion of lanosterol to cholesterol is a multistep
process, resulting in the shortening of the carbon chain
from 30 to 27 carbons, removal of the two methyl groups
at C-4, migration of the double bond from C-8 to C-5,
and reduction of the double bond between C-24 and C25.
• [Note: This pathway includes more than 19 different
enzymatic reactions. Smith-Lemli-Opitz syndrome
(SLOS), a relatively common autosomal recessive
disorder of cholesterol biosynthesis, is caused by a
partial deficiency in 7-dehydrocholesterol-7-reductase—
an enzyme involved in the migration of the double bond.
SLOS is one of several multisystem, embryonic
malformation syndromes associated with impaired
cholesterol synthesis.]
• Figure 18.5 Synthesis of cholesterol from mevalonic
acid.
D. Regulation of cholesterol synthesis
• HMG CoA reductase, the rate-limiting enzyme, is the
major control point for cholesterol biosynthesis, and is
subject to different kinds of metabolic control.
1. Sterol-dependent regulation of gene expression:
• Expression of the HMG CoA reductase gene is
controlled by the transcription factor, SREBP (sterol
regulatory element–binding protein) that binds DNA at
the cis-acting sterol regulatory element (SRE) of the
reductase gene.
• SREBP is an integral protein of the ER membrane, and
associates with a second ER membrane protein, SCAP
(SREBP cleavage–activating protein).
•
Figure 18.6 Regulation of HMG CoA reductase. SRE = sterol regulatory
element; SREBP = sterol regulatory element binding protein; SCAP =
SREBP cleavage-activating protein
2. Sterol-accelerated enzyme degradation:
• The reductase itself is an integral protein of the ER
membrane. When sterol levels in the cell are high, the
reductase binds to insig proteins. This binding leads to
ubiquitination and proteasomal degradation of the
reductase.
3. Sterol-independent phosphorylation/dephosphorylation:
• HMG CoA reductase activity is controlled covalently
through the actions of adenosine monophosphate
(AMP)–activated protein kinase (AMPK), and a
phosphoprotein phosphatase.
• The phosphorylated form of the enzyme is inactive,
whereas the dephosphorylated form is active.
• [Note: AMPK is activated by AMP, so cholesterol
synthesis, like fatty acid synthesis, is decreased
when ATP availability is decreased.]
4. Hormonal regulation:
• The amount (and, therefore, the activity) of HMG
CoA reductase is controlled hormonally.
• An increase in insulin favors up-regulation of the
expression of the HMG CoA reductase gene.
Glucagon has the opposite effect.
5. Inhibition by drugs:
• The statin drugs (atorvastatin, fluvastatin,
lovastatin, pravastatin, rosuvastatin, and
simvastatin) are structural analogs of HMG CoA,
and are (or are metabolized to) reversible,
competitive inhibitors of HMG CoA reductase.
• They are used to decrease plasma cholesterol
levels in patients with hypercholesterolemia
• Figure 18.7 Structural similarity
of HMG and simvastatin, a
clinically useful cholesterollowering drug of the “statin”
family.
IV. Degradation of Cholesterol
• The ring structure of cholesterol cannot be metabolized
to CO2 and H2O in humans.
• Rather, the intact sterol nucleus is eliminated from the
body by conversion to bile acids and bile salts, which are
excreted in the feces, and by secretion of cholesterol into
the bile, which transports it to the intestine for
elimination.
• Some of the cholesterol in the intestine is modified by
bacteria before excretion. The primary compounds made
are the isomers coprostanol and cholestanol, which are
reduced derivatives of cholesterol.
• Together with cholesterol, these compounds make up
the bulk of neutral fecal sterols.
V. Bile Acids and Bile Salts
• Bile consists of a watery mixture of organic and
inorganic compounds.
• Phosphatidylcholine (lecithin) and bile salts
(conjugated bile acids) are quantitatively the
most important organic components of bile.
• Bile can either pass directly from the liver where
it is synthesized into the duodenum through the
common bile duct, or be stored in the
gallbladder when not immediately needed for
digestion.
A. Structure of the bile acids
• The bile acids contain 24 carbons, with two or three
hydroxyl groups and a side chain that terminates in a
carboxyl group.
• The carboxyl group has a pKa of about six and,
therefore, is not fully ionized at physiologic pH—hence,
the term “bile acid.”
• The bile acids are amphipathic in that the hydroxyl
groups are α in orientation (they lie “below” the plane of
the rings) and the methyl groups are β (they lie “above”
the plane of the rings).
• Therefore, the molecules have both a polar and a
nonpolar face, and can act as emulsifying agents in the
intestine, helping prepare dietary triacylglycerol and
other complex lipids for degradation by pancreatic
digestive enzymes.
B. Synthesis of bile acids
• Bile acids are synthesized in the liver by a multistep,
multiorganelle pathway in which hydroxyl groups are
inserted at specific positions on the steroid structure, the
double bond of the cholesterol B ring is reduced, and the
hydrocarbon chain is shortened by three carbons,
introducing a carboxyl group at the end of the chain.
• The most common resulting compounds, cholic acid (a
triol) and chenodeoxycholic acid (a diol), are called
“primary” bile acids.
• [Note: The rate-limiting step in bile acid synthesis is the
introduction of a hydroxyl group at carbon 7 of the
steroid nucleus by cholesterol-7-α-hydroxylase, an ERassociated cytochrome P450 (CYP) enzyme found only
in liver. The enzyme is down-regulated by cholic acid
and up-regulated by cholesterol]
• Figure 18.8 Bile acids.
• Figure 18.9 Synthesis of
cholic acid, a bile acid.
C. Synthesis of bile salts
• Before the bile acids leave the liver, they are conjugated
to a molecule of either glycine or taurine (an endproduct
of cysteine metabolism) by an amide bond between the
carboxyl group of the bile acid and the amino group of
the added compound.
• These new structures are called bile salts and include
glycocholic and glycochenodeoxycholic acids, and
taurocholic and taurochenodeoxycholic acids.
• The ratio of glycine to taurine forms in the bile is
approximately 3:1.
• Addition of glycine or taurine results in the presence of a
carboxyl group with a lower pKa (from glycine) or a
sulfonate group (from taurine), both of which are fully
ionized (negatively charged) at physiologic pH.
• Bile salts are more effective detergents than bile acids
because of their enhanced amphipathic nature.
• Therefore, only the conjugated forms—that is, the bile
salts—are found in the bile.
• Individuals with genetic deficiencies in the conversion of
cholesterol to bile acids are treated with exogenously
supplied chenodeoxycholic acid.
[Bile salts provide the only significant mechanism for
cholesterol excretion, both as a metabolic product of
cholesterol and as a solubilizer of cholesterol in bile].
• Figure 18.10 Bile salts. [Note “cholic” in the
names.]
D. Action of intestinal flora on bile salts
• Bacteria in the intestine can remove glycine and
taurine from bile salts, regenerating bile acids.
• They can also convert some of the primary bile
acids into “secondary” bile acids by removing a
hydroxyl group, producing deoxycholic acid from
cholic acid and lithocholic acid from
chenodeoxycholic acid (Figure 18.11).
Figure 18.11 Enterohepatic circulation of bile salts and bile
acids.
E. Enterohepatic circulation
• Bile salts secreted into the intestine are efficiently
reabsorbed (greater than 95%) and reused.
• The mixture of primary and secondary bile acids and bile
salts is absorbed primarily in the ileum.
• They are actively transported from the intestinal mucosal
cells into the portal blood, and are efficiently removed by
the liver parenchymal cells.
• [Note: Bile acids are hydrophobic and require a carrier in
the portal blood. Albumin carries them in a noncovalent
complex, just as it transports fatty acids in blood.]
• The liver converts both primary and secondary bile acids
into bile salts by conjugation with glycine or taurine, and
secretes them into the bile.
• The continuous process of secretion of bile salts into the
bile, their passage through the duodenum where some
are converted to bile acids, and their subsequent return
to the liver as a mixture of bile acids and salts is termed
the enterohepatic circulation.
• Between 15 and 30 g of bile salts are secreted from the
liver into the duodenum each day, yet only about 0.5 g is
lost daily in the feces.
• Approximately 0.5 g/day is synthesized from cholesterol
in the liver to replace the lost bile acids. Bile acid
sequestrants, such as cholestyramine, bind bile acids in
the gut, prevent their reabsorption, and so promote their
excretion.
• They are used in the treatment of hypercholesterolemia
because the removal of bile acids relieves the inhibition
on bile acid synthesis in the liver, thereby diverting
additional cholesterol into that pathway.
• [Note: Dietary fiber also binds bile acids and increases
their excretion.]
Figure 18.11 Enterohepatic circulation of bile salts and bile
acids.
F. Bile salt deficiency: cholelithiasis
• The movement of cholesterol from the liver into the bile
must be accompanied by the simultaneous secretion of
phospholipid and bile salts.
• If this dual process is disrupted and more cholesterol
enters the bile than can be solubilized by the bile salts
and lecithin present, the cholesterol may precipitate in
the gallbladder, initiating the occurrence of cholesterol
gallstone disease—cholelithiasis.
• This disorder is typically caused by a decrease of bile
acids in the bile, which may result from:
1) gross malabsorption of bile acids from the intestine,
as seen in patients with severe ileal disease;
2) obstruction of the biliary tract, interrupting the
enterohepatic circulation;
3) severe hepatic dysfunction, leading to decreased
synthesis of bile salts, or other abnormalities in bile
production; or
4) excessive feedback suppression of bile acid synthesis
as a result of an accelerated rate of recycling of bile
acids.
• Cholelithiasis also may result from increased biliary
cholesterol excretion, as seen with the use of fibrates.
• [Note: Fibrates, such as gemfibrozil, are derivatives of
fibric acid. They are used to reduce triacylglycerol levels
in blood through up-regulation of fatty acid β-oxidation.]
• Laparoscopic cholecystectomy (surgical removal of the
gallbladder through a small incision) is currently the
treatment of choice.
• However, for patients who are unable to undergo
surgery, administration of chenodeoxycholic acid to
supplement the body's supply of bile acids results in a
gradual (months to years) dissolution of the gallstones.
•
Figure 18.12 Gallbladder
with gallstones
VI. Plasma Lipoproteins
• The plasma lipoproteins are spherical
macromolecular complexes of lipids and specific
proteins (apolipoproteins or apoproteins).
• The lipoprotein particles include chylomicrons,
very-low-density lipoproteins (VLDL), lowdensity lipoproteins (LDL), and high-density
lipoproteins (HDL).
• They differ in lipid and protein composition, size,
density, and site of origin.
• Lipoproteins function both to keep their
component lipids soluble as they transport them
in the plasma and to provide an efficient
mechanism for transporting their lipid contents to
(and from) the tissues.
• In humans, the transport system is less perfect
than in other animals and, as a result, humans
experience a gradual deposition of lipid—
especially cholesterol—in tissues.
• This is a potentially life-threatening occurrence
when the lipid deposition contributes to plaque
formation, causing the narrowing of blood
vessels (atherosclerosis).
Figure 18.13 Approximate size
and density of serum
lipoproteins. Each family of
lipoproteins exhibits a range of
sizes and densities; this figure
shows typical values. The width
of the rings approximates the
amount of each component.
[Note: Although cholesterol and
its esters are shown as one
component in the center of each
particle, physically cholesterol is
a surface component whereas
cholesteryl esters are located in
the interior of the lipoproteins.]
A. Composition of plasma lipoproteins
• Lipoproteins are composed of a neutral lipid core
(containing triacylglycerol, and cholesteryl esters)
surrounded by a shell of amphipathic apolipoproteins,
phospholipid, and nonesterified cholesterol.
• These amphipathic compounds are oriented so that their
polar portions are exposed on the surface of the
lipoprotein, thus making the particle soluble in aqueous
solution.
• The triacylglycerol and cholesterol carried by the
lipoproteins are obtained either from the diet (exogenous
source) or from de novo synthesis (endogenous source).
• [Note: Lipoprotein particles constantly interchange lipids
and apolipoproteins with each other; therefore, the actual
apolipoprotein and lipid content of each class of particles
can be somewhat variable.]
1. Size and density of lipoprotein particles:
• Chylomicrons are the lipoprotein particles lowest
in density and largest in size, and contain the
highest percentage of lipid and the lowest
percentage of protein.
• VLDLs and LDLs are successively denser,
having higher ratios of protein to lipid. HDL
particles are the densest.
• Plasma lipoproteins can be separated on the
basis of their electrophoretic mobility, as shown
in Figure 18.15, or on the basis of their density
by ultracentrifugation.
• Figure 18.14 Structure of a
typical lipoprotein particle.
• Figure 18.15 Electrophoretic mobility of plasma lipoproteins. The
order of LDL and VLDL is reversed if ultracentrifugation is used as
the separation technique.
2. Apolipoproteins:
• The apolipoproteins associated with lipoprotein particles
have a number of diverse functions, such as providing
recognition sites for cell-surface receptors, and serving
as activators or coenzymes for enzymes involved in
lipoprotein metabolism.
• Some of the apolipoproteins are required as essential
structural components of the particles and cannot be
removed (in fact, the particles cannot be produced
without them), whereas others are transfered freely
between lipoproteins.
• Apolipoproteins are divided by structure and function into
five major classes, A through E, with most classes
having subclasses, for example, apolipoprotein (or apo)
A-I and apo C-II.
• [Note: Functions of all of the apolipoproteins are not yet
known.]
B. Metabolism of chylomicrons
• Chylomicrons are assembled in intestinal
mucosal cells and carry dietary
triacylglycerol, cholesterol, fat-soluble
vitamins, and cholesteryl esters (plus
additional lipids made in these cells) to the
peripheral tissues.
• [Note: TAGs account for close to 90% of
the lipids in a chylomicron.]
•
Figure 18.16 Metabolism of chylomicrons. CM = chylomicron; TAG =
triacylglycerol; C = cholesterol; CE = cholesteryl esters. Apo B-48, apo C-II,
and apo E are apolipoproteins found as specific components of plasma
lipoproteins. The lipoproteins are not drawn to scale (see Figure 18.13 for
details of the size and density of lipoproteins).
1.
•
•
•
Synthesis of apolipoproteins:
Apolipoprotein B-48 is unique to chylomicrons.
Its synthesis begins on the rough ER; it is glycosylated
as it moves through the RER and Golgi.
[Note: Apo B-48 is so named because it constitutes the
N-terminal, 48% of the protein coded for by the apo B
gene. Apo B-100, which is synthesized by the liver and
found in VLDL and LDL, represents the entire protein
coded for by the apo B gene. Posttranscriptional
editing of a cytosine to a uracil in intestinal apo B-100
mRNA creates a nonsense codon, allowing translation
of only 48% of the mRNA.].
2. Assembly of chylomicrons:
• The enzymes involved in triacylglycerol,
cholesterol, and phospholipid synthesis are
located in the smooth ER.
• Assembly of the apolipoproteins and lipid into
chylomicrons requires microsomal triacylglycerol
transfer protein, which loads apo B-48 with lipid.
• This occurs before transition from the ER to the
Golgi, where the particles are packaged in
secretory vesicles.
• These fuse with the plasma membrane releasing
the lipoproteins, which then enter the lymphatic
system and, ultimately, the blood.
3. Modification of nascent chylomicron particles:
• The particle released by the intestinal mucosal cell is
called a “nascent” chylomicron because it is functionally
incomplete.
• When it reaches the plasma, the particle is rapidly
modified, receiving apo E (which is recognized by
hepatic receptors) and C apolipoproteins.
• The latter include apo C-II, which is necessary for the
activation of lipoprotein lipase, the enzyme that degrades
the triacylglycerol contained in the chylomicron.
• The source of these apolipoproteins is circulating HDL.
•
Figure 18.16 Metabolism of chylomicrons. CM = chylomicron; TAG =
triacylglycerol; C = cholesterol; CE = cholesteryl esters. Apo B-48, apo C-II,
and apo E are apolipoproteins found as specific components of plasma
lipoproteins. The lipoproteins are not drawn to scale (see Figure 18.13 for
details of the size and density of lipoproteins).
4. Degradation of triacylglycerol by lipoprotein lipase:
• Lipoprotein lipase is an extracellular enzyme that is
anchored by heparan sulfate to the capillary walls of
most tissues, but predominantly those of adipose tissue
and cardiac and skeletal muscle.
• Adult liver does not have this enzyme.
• [Note: A hepatic lipase is found on the surface of
endothelial cells of the liver. However, it does not
significantly attack chylomicrons or VLDL triacylglycerol,
but rather assists with HDL metabolism]
• Lipoprotein lipase, activated by apo C-II on circulating
lipoprotein particles, hydrolyzes the triacylglycerol
contained in these particles to yield fatty acids and
glycerol.
• The fatty acids are stored (by the adipose) or
used for energy (by the muscle). If they are not
immediately taken up by a cell, the long-chain
fatty acids are transported by serum albumin
until their uptake does occur.
• Glycerol is used by the liver, for example, in lipid
synthesis, glycolysis, or gluconeogenesis.
• [Note: Patients with a deficiency of lipoprotein
lipase or apo C-II (Type 1 hyperlipoproteinemia,
or familial lipoprotein lipase deficiency) show a
dramatic accumulation (1000 mg/dl or greater)
of chylomicrons in the plasma
(hypertriacylglycerolemia), even in the fasted
state.]
5. Regulation of lipoprotein lipase activity:
• Lipoprotein lipase synthesis and transfer to the luminal
surface of the capillary is stimulated by insulin (signifying
a fed state).
• Furthermore, isomers of lipoprotein lipase have different
Km values for triacylglycerol.
• For example, the adipose enzyme has a large Km,
allowing the removal of fatty acids from circulating
lipoprotein particles and their storage as triacylglycerols
only when plasma lipoprotein concentrations are
elevated.
• Conversely, heart muscle lipoprotein lipase has a small
Km, allowing the heart continuing access to the
circulating fuel, even when plasma lipoprotein
concentrations are low.
• [Note: The highest concentration of lipoprotein lipase is
in cardiac muscle, reflecting the use of fatty acids to
provide much of the energy needed for cardiac function.]
6. Formation of chylomicron remnants:
• As the chylomicron circulates and more than 90% of the
triacylglycerol in its core is degraded by lipoprotein
lipase, the particle decreases in size and increases in
density.
• In addition, the C apoproteins (but not apo E) are
returned to HDL.
• The remaining particle, called a “remnant,” is rapidly
removed from the circulation by the liver, whose cell
membranes contain lipoprotein receptors that recognize
apo E.
• Chylomicron remnants bind to these receptors and are
taken into the hepatocytes by endocytosis.
• The endocytosed vesicle then fuses with a lysosome,
and the apolipoproteins, cholesteryl esters, and other
components of the remnant are hydrolytically degraded,
releasing amino acids, free cholesterol, and fatty acids.
• The receptor is recycled.
•
Figure 18.16 Metabolism of chylomicrons. CM = chylomicron; TAG =
triacylglycerol; C = cholesterol; CE = cholesteryl esters. Apo B-48, apo C-II,
and apo E are apolipoproteins found as specific components of plasma
lipoproteins. The lipoproteins are not drawn to scale (see Figure 18.13 for
details of the size and density of lipoproteins).
C. Metabolism of VLDL
• VLDLs are produced in the liver.
• They are composed predominantly of triacylglycerol
(approximately 60%), and their function is to carry this
lipid from the liver to the peripheral tissues.
• There, the triacylglycerol is degraded by lipoprotein
lipase, as discussed for chylomicrons.
• [Note: “Fatty liver” (hepatic steatosis) occurs in conditions
in which there is an imbalance between hepatic
triacylglycerol synthesis and the secretion of VLDL.
• Such conditions include obesity, uncontrolled diabetes
mellitus, and chronic ethanol ingestion.]
•
Figure 18.17 Metabolism of VLDL and LDL. TAG = triacylglycerol; VLDL = very-low-density
lipoprotein; LDL = low-density-lipoprotein; IDL = intermediate-density lipoprotein; C = cholesterol;
CE = cholesteryl esters. Apo B-100, apo C-II, and apo E are apolipoproteins found as specific
components of plasma lipoproteins. Lipoproteins are not drawn to scale (see Figure 18.13 for
details of the size and density of lipoproteins).
1. Release of VLDL:
• VLDL are secreted directly into the blood by the
liver as nascent VLDL particles containing apo
B-100.
• They must obtain apo C-II and apo E from
circulating HDL (see Figure 18.17). As with
chylomicrons, apo C-II is required for activation
of lipoprotein lipase.
• [Note: Abetalipoproteinemia is a rare
hypolipoproteinemia caused by a defect in
microsomal triacylglycerol transfer protein,
leading to an inability to load apo B with lipid. As
a consequence, no VLDL or chylomicrons are
formed, and triacylglycerols accumulate in the
liver and intestine.]
• Figure 18.18 Transfer of
cholesteryl esters (CE)
from HDL to VLDL in
exchange for triacylglycerol
(TAG) or phospholipids
(PL).
2. Modification of circulating VLDL:
• As VLDL pass through the circulation, triacylglycerol is
degraded by lipoprotein lipase, causing the VLDL to
decrease in size and become denser.
• Surface components, including the C and E apoproteins,
are returned to HDL, but the particles retain apo B-100.
• Finally, some triacylglycerols are transferred from VLDL
to HDL in an exchange reaction that concomitantly
transfers some cholesteryl esters from HDL to VLDL.
• This exchange is accomplished by cholesteryl ester
transfer protein (Figure 18.18).
• Figure 18.18 Transfer of
cholesteryl esters (CE)
from HDL to VLDL in
exchange for triacylglycerol
(TAG) or phospholipids
(PL).
3. Production of LDL from VLDL in the
plasma:
• With these modifications, the VLDL is
converted in the plasma to LDL.
• Intermediate-sized particles, the
intermediate-density lipoproteins (IDL) or
VLDL remnants, are observed during this
transition.
• IDLs can also be taken up by cells through
receptor-mediated endocytosis that uses
apo E as the ligand.
[Note:
• Apo E is normally present in three isoforms, E-2, E-3,
and E-4.
• Apo E2 binds poorly to receptors, and patients who are
homozygotic for apo E2 are deficient in the clearance of
chylomicron remnants and IDL.
• The individuals have familial Type III
hyperlipoproteinemia (familial dysbetalipoproteinemia, or
broad beta disease), with hypercholesterolemia and
premature atherosclerosis.
• Not yet understood is the fact that the E-4 isoform
confers increased susceptibility to and decreased age of
onset of late-onset Alzheimer disease, doubling the
lifetime risk.]
D. Metabolism of LDL
•
LDL particles contain much less triacylglycerol than
their VLDL predecessors, and have a high
concentration of cholesterol and cholesteryl esters
(Figure 18.19).
1.
–
–
–
–
–
Receptor-mediated endocytosis: The primary function of LDL
particles is to provide cholesterol to the peripheral tissues (or
return it to the liver).
They do so by binding to cell surface membrane LDL
receptors that recognize apo B-100 (but not apo B-48).
Because these LDL receptors can also bind apo E, they are
known as apo B-100/apo E receptors.
A summary of the uptake and degradation of LDL particles is
presented in Figure 18.20.
[Note: The numbers in brackets below refer to corresponding
numbers on that figure.]
A similar mechanism of receptor-mediated endocytosis is used
for the cellular uptake and degradation of chylomicron
remnants and IDLs by the liver.
Figure 18.19 Composition of the plasma lipoproteins.
Note the high concentration of cholesterol and
cholesteryl esters in LDL.
[1] LDL receptors are negatively charged glycoproteins that
are clustered in pits on cell membranes. The intracellular
side of the pit is coated with the protein clathrin, which
stabilizes the shape of the pit.
[2] After binding, the LDL-receptor complex is internalized
by endocytosis.
[Note: A deficiency of functional LDL receptors causes a
significant elevation in plasma LDL and, therefore, of
plasma cholesterol. Patients with such deficiencies have
Type II hyperlipidemia (familial hypercholesterolemia)
and premature atherosclerosis.]
[3] The vesicle containing the LDL rapidly loses its clathrin
coat and fuses with other similar vesicles, forming larger
vesicles called endosomes.
[4] The pH of the endosome falls (due to the proton-pumping
activity of endosomal ATPase), which allows separation of the
LDL from its receptor.
- The receptors then migrate to one side of the endosome,
whereas the LDLs stay free within the lumen of the vesicle.
[Note: This structure is called CURL—the Compartment for
Uncoupling of Receptor and Ligand.]
[5] The receptors can be recycled, whereas the lipoprotein
remnants in the vesicle are transferred to lysosomes and
degraded by lysosomal (hydrolytic) enzymes, releasing free
cholesterol, amino acids, fatty acids, and phospholipids.
- These compounds can be reutilized by the cell.
[Note: Rare autosomal recessive deficiencies in the ability to
hydrolyze lysosomal cholesteryl esters (Wolman disease), or
to transport unesterified cholesterol out of the lysosome
(Niemann-Pick disease, type C) have been identified.]
Figure 18.20 Cellular
uptake and degradation
of LDL. ACAT = acyl
CoA:cholesterol
acyltransferase.
2. Effect of endocytosed cholesterol on cellular
cholesterol homeostasis:
- The chylomicron remnant-, IDL-, and LDL-derived
cholesterol affects cellular cholesterol content in
several ways (see Figure 18.20).
- First, HMG CoA reductase is inhibited by high
cholesterol, as a result of which, de novo cholesterol
synthesis decreases.
- Second, synthesis of new LDL receptor protein is
reduced by decreasing the expression of the LDL
receptor gene, thus limiting further entry of LDL
cholesterol into cells.
[Note: Regulation of the LDL receptor gene involves a
SRE and a SREBP, as was seen in the regulation of the
gene for HMG CoA reductase (see p. 223).]
- Third, if the cholesterol is not required immediately for
some structural or synthetic purpose, it is esterified by
acyl CoA:cholesterol acyltransferase (ACAT).
- ACAT transfers a fatty acid from a fatty acyl CoA
derivative to cholesterol, producing a cholesteryl ester
that can be stored in the cell (Figure 18.21).
- The activity of ACAT is enhanced in the presence of
increased intracellular cholesterol.
•
Figure 18.21 Synthesis of
intracellular cholesteryl ester
by ACAT.
3. Uptake of chemically modified LDL by macrophage
scavenger receptors:
- In addition to the highly specific and regulated receptormediated pathway for LDL uptake described above,
macrophages possess high levels of scavenger receptor
activity.
- These receptors, known as scavenger receptor class A
(SR-A), can bind a broad range of ligands, and mediate
the endocytosis of chemically modified LDL in which the
lipid components or apo B have been oxidized.
- Unlike the LDL receptor, the scavenger receptor is not
down-regulated in response to increased intracellular
cholesterol.
- Cholesteryl esters accumulate in macrophages and
cause their transformation into “foam” cells, which
participate in the formation of atherosclerotic plaque
(Figure 18.22).
• Figure 18.22 Role of oxidized lipoproteins in plaque
formation in arterial wall.
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.
2.
•
•
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).
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.]
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.
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).
• 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 cell-surface 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 lipidpoor 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.]
• [Note: Hepatic lipase, with its ability to degrade
both TAG and phospholipids, participates in the
conversion of HDL2 to 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.
• 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.]
VII. 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.
• 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, corticosteroidbinding globulin (transcortin) is responsible for
transporting cortisol, and sex hormone–binding
protein transports sex steroids.
• A number of genetic diseases are caused by
deficiencies in specific steps in the biosynthesis
of steroid hormones. Some representative
diseases are described in Figure 18.25.
Figure 18.24 Key
steroid hormones.
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).
• [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 (see Figure 18.25).
• 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.
• A defect in the activity or amount of an enzyme
in this pathway can lead to a deficiency in the
synthesis of hormones beyond the affected step,
and to an excess in the hormones or metabolites
before that step.
• Because all members of the pathway have
potent biologic activity, serious metabolic
imbalances occur if enzyme deficiencies are
present (see Figure 18.25).
• Collectively these disorders are known as the
congenital adrenal hyperplasias.
Figure 18.25
Steroid hormone
synthesis and
associated
diseases.
B. Secretion of adrenal cortical steroid hormones
• Steroid hormones are secreted on demand from their
tissues of origin in response to hormonal signals.
• The corticosteroids and androgens are made in different
regions of the adrenal cortex, and are secreted into
blood in response to different signals.
1. Cortisol: Its secretion from the middle layer (zona
fasciculata) of the adrenal cortex is controlled by the
hypothalamus, to which the pituitary gland is attached
(Figure 18.26).
• In response to severe stress (for example, infection),
corticotropin-releasing hormone (CRH), produced by the
hypothalamus, travels through a network of capillaries to
the anterior lobe of the pituitary, where it induces the
production and secretion of adrenocorticotropic hormone
(ACTH, or corticotropin).
• The polypeptide ACTH, often called the “stress
hormone,” stimulates the adrenal cortex to synthesize
and secrete the glucocorticoid cortisol.
• Cortisol allows the body to respond to stress through its
effects on intermediary metabolism and the inflammatory
response.
• As cortisol levels rise, the release of CRH and ACTH is
inhibited.
• [Note: ACTH binds to a plasma membrane receptor. Its
intracellular effects are mediated through a second
messenger, cyclic AMP (cAMP).]
2. Aldosterone:
• This hormone's secretion from the outer layer (zona
glomerulosa) of the adrenal cortex is induced by a
decrease in the plasma Na+/K+ ratio, and by the
hormone, angiotensin II.
• Angiotensin II is produced from angiotensin I by
angiotensin-converting enzyme (ACE), an enzyme found
predominantly in the lungs, but which is also distributed
widely in the body.
• [Note: Angiotensin I, an octapeptide, is produced in the
blood by cleavage of an inactive precursor,
angiotensinogen, secreted by the liver. Cleavage is
accomplished by the enzyme renin, made and secreted
by the kidney.]
Estrogen is derived from testosterone by aromatase (CYP19). Aromatase
inhibitors are used in the treatment of estrogen-responsive breast cancer in
post-menopausal women.
• Angiotensin II binds to cell-surface receptors.
• However, in contrast to ACTH, its effects are
mediated through the phosphatidylinositol 4,5bisphosphate (PIP2) pathway (see p. 205) and
not by cAMP.
• Aldosterone's primary effect is on the kidney
tubules, where it stimulates sodium uptake and
potassium excretion (Figure 18.27).
• [Note: An effect of aldosterone is an increase in
blood pressure. Competitive inhibitors of ACE
are used to treat renin-dependent hypertension.]
3. Androgens:
• Both the inner (zona reticularis) and middle
layers of the adrenal cortex produce
androgens, primarily dehydroepiandrosterone
and androstenedione.
• Although adrenal androgens themselves are
weak, they are converted in peripheral tissues
to testosterone—a strong androgen—and to
estradiol.
Figure 18.26 Pituitary
hormone stimulation of
steroid hormone
synthesis and
secretion.
C. Secretion of steroid hormones from gonads
• The testes and ovaries synthesize hormones necessary
for physical development and reproduction.
• A single hypothalamic-releasing factor, gonadotropinreleasing hormone, stimulates the anterior pituitary to
release the glycoproteins, luteinizing hormone (LH) and
follicle-stimulating hormone (FSH).
• Like ACTH, LH and FSH bind to surface receptors and
cause an increase in cAMP.
• LH stimulates the testes to produce testosterone and the
ovaries to produce estrogens and progesterone (see
Figure 18.27).
• FSH regulates the growth of ovarian follicles and
stimulates testicular spermatogenesis.
• [Note: For maximum effect on the male or female gonad,
FSH also requires the presence of LH.]
D. Mechanism of steroid hormone action
• Each steroid hormone diffuses across the plasma
membrane of its target cell and binds to a specific
cytosolic or nuclear receptor.
• These receptor–ligand complexes accumulate in the
nucleus, dimerize, and bind to specific regulatory DNA
sequences (hormone-response elements, HRE) in
association with coactivator proteins, thereby causing
promoter activation and increased transcription of
targeted genes (Figure 18.28).
• An HRE is found in the promoter (or an enhancer
element, see p. 423) for genes that respond to a specific
steroid hormone, thus ensuring coordinated regulation of
these genes.
• Hormone–receptor complexes can also inhibit
transcription in association with corepressors.
• [Note: The binding of a hormone to its receptor
causes a conformational change in the receptor
that uncovers its DNA-binding domain, allowing
the complex to interact through a zinc-finger
motif with the appropriate sequence on the DNA.
• It is recognized that the receptors for the diverse
group of steroid hormones, plus those for thyroid
hormone, retinoic acid, and 1,25dihydroxycholecalciferol (Vitamin D), are
members of a “superfamily” of structurally
related gene regulators that function in a similar
way.]
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 (from 3′phosphoadenosyl-5′-phosphosulfate, see p. 162).
• 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.
Figure 18.27 Actions of steroid
hormones.
VIII. 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.
• 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.
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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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 liver-synthesized plasma enzyme
that is activated by apo A-1; and
3) delivering these cholesteryl esters to the liver
(“reverse cholesterol transport”).
• Cholesterol is the precursor of all classes of steroid
hormones (glucocorticoids, mineralocorticoids, and sex
hormones—androgens, estrogens, and progestins).
• Synthesis, using primarily cytochrome P450 (CYP)
mixed function oxidases, occurs in the adrenal cortex
(cortisol, aldosterone, and androgens), ovaries and
placenta (estrogens and progestins), and testes
(testosterone).
• Each steroid hormone diffuses across the plasma
membrane of its target cell and binds to a specific
cytosolic or nuclear receptor.
• These receptor–ligand complexes accumulate in the
nucleus, dimerize, and bind to specific regulatory DNA
sequences (hormone-response elements) in association
with coactivator proteins, thereby causing promoter
activation and increased transcription of targeted genes.
• In association with corepressors, transcription is
decreased.
Figure 18.28 Activation of
transcription by interaction of
steroid hormone-receptor
complex with hormone
response element (HRE).