Summary of cholesterol metabolism

Synthesis of cholesterol occurs in the

cytoplasm of most tissues, but the liver,
intestine, adrenal cortex, and
steroidogenic reproductive tissues are
the most active.

Acetate, via acetyl CoA, is the initial

precursor for cholesterol synthesis.
1) condensation of three acetate units to

form a six-carbon intermediate, mevalonate;

2) conversion of mevalonate to activated

isoprene units;

3) polymerization of six 5-carbon isoprene

units to form the 30-carbon linear squalene;

4) cyclization of squalene to form the four

rings of the steroid nucleus, with a further

series of changes (oxidations, removal or

migration of methyl groups) to produce

cholesterol.
The cytosolic HMG-CoA synthase in
this pathway is distinct from the
mitochondrial isoenzyme that
catalyzes HMG-CoA synthesis in ketone
body formation
 The first step in this sequence is

catalyzed by a mixed-function oxidase

(a monooxygenase), for which the co-

substrate is NADPH. The product is an

epoxide, which in the next step is

cyclized to the steroid nucleus. The final

product of these reactions in animal cells

is cholesterol;

HMG-CoA raducta11 is inhibited by cholesterol In the liver; it is also inhibited

by bile salts and is induced when blood insulin levels are elevated. It is also
regulated by phosphorylation by the AMP-activated protein kinase {the
phosphorylated enzyme bas reduced activity).
Regulation of HMG-CoA reductase.
SRE = sterol regulatory element; SREBP = sterol regulatory element–binding protein;
SCAP = SREBP cleavage –activating protein;

1. Enzyme activity is controlled by reversible phosphorylation/dephosphorylation in

response to AMP, ie, cholesterol synthesis is suppressed when energy levels are low.

2. Expression of the HMG CoA reductase gene is controlled by a steroldependent

transcription factor, which increases enzyme synthesis in response to low cholesterol
levels.
Sterol-accelerated enzyme degradation:
The reductase itself is a sterol-sensing integral protein of the ER membrane. When sterol
levels in the cell are high, the enzyme binds to INSIG proteins .[ insulin-induced gene]
Binding leads to ubiquitination and proteasomal degradation of the reductase
Hormonal regulation:
An increase in insulin and thyroxine favors upregulation of the expression of the gene for
the reductase. Glucagon and the glucocorticoids have the opposite effect.

Inhibition by drugs :

The statin drugs (atorvastatin, fluvastatin,

lovastatin 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
 Lipoproteins: Transport of Lipids
• In general, lipoproteins are spherical particles with an outer surface of polar proteins and

glycerophospholipids that surround hundreds of nonpolar molecules of triacylglycerols and

cholesteryl esters. Cholesteryl esters are the prevalent form of cholesterol in the blood. They

are formed by the esterification of the hydroxyl group in cholesterol with a fatty acid.
CMs, formed in intestinal cells and secreted into the lymphatic system, are the LP particles that transport
dietary lipids (and fat-soluble vitamins) through the blood.
Apolipoprotein ( apo) B-48 is the characteristic surface protein of CMs. [ Note:PLs are also found on the surface.]

Muscle and adipose tissues are the primary sites for degradation of TAGs carried by CMs.
LPL, located on the endothelial surface of capillaries in muscle and adipose tissue, degrades
the TAGs. LPLrequires activation by apo CII located on CM surfaces.
The FA products are taken in by muscles (for energy) and adipocytes (for storage) and
are transported on serum albumin, taken up, and used by the liver. The glycerol is picked
up by liver and phosphorylated to glycerol 3-P, which can be used in hepatic TAG synthesis, for example.
 High-density lipoprotein (HDL), originates in the liver and small intestine as small, protein-rich particles
that contain relatively little cholesterol and no cholesteryl esters. HDLs contain apoA-I, apoC-I, apoC-II, and other
apolipoproteins, as well as the enzyme lecithin-cholesterol acyl transferase (LCAT), which catalyzes the formation of
cholesteryl esters from lecithin (phosphatidylcholine) and cholesterol. LCAT on the surface of nascent (newly forming)
HDL particles converts the cholesterol and phosphatidylcholine of chylomicron and VLDL remnants to cholesteryl
esters, which begin to form a core, transforming the disk-shaped nascent HDL to a mature, spherical HDL particle. This
cholesterol-rich lipoprotein then returns to the liver, where the cholesterol is unloaded; some of this cholesterol is
converted to bile salts
 HDL may be taken up in the liver by receptormediated endocytosis, but at least some of the
cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane
receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors
mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell.
Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and
VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the
liver, in reverse cholesterol transport pathways. In one reverse transport path, interaction of nascent HDL with
SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL,
which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL interacts with an active
transporter, the ABC1 protein, in a cholesterol-rich cell. The apoA-I (and presumably the HDL) is taken up by
endocytosis, then resecreted with a load of cholesterol, which it transports to the liver. The ABC1 protein is a
member of a large family of multidrug transporters, sometimes called ABC transporters because they all have
ATP-binding cassettes; they also have two transmembrane domains with six transmembrane helices. These
proteins actively transport a variety of ions, amino acids, vitamins, steroid hormones, and bile salts across
plasma membranes.
 Bile acids are synthesized in the
liver by a multistep, multiorganelle
pathway in which hydroxyl groups a
reinserted at specific positions
on the steroid structure; the double bond of
the cholesterol B ring is
re duce d; 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),

The bile acids contain 24 carbons , with two

or three hydroxyl groups and a side chain

that terminates in a carboxyl group.

The rate-limiting and regulated enzyme of BA
synthesis is cholesterol 7- α-hydroxylase.
Note: The products, the primary BAs, undergo
hepatic conjugation with taurine or Gly and form
conjugated BAs that are stored in the gallbladder
and released by CCK(cholecystokinin).
At the pH of bile, the conjugated derivatives are
negatively charged, contributing to
their amphipathic nature, and are termed BSs.
Intestinal bacteria can dehydroxylate them,
generating secondary BSs.
Regulation is transcriptional: BAs (via a nuclear
receptor) cause decreased transcription of the
gene for the hydroxylase.
 P-450 Oxygenases
• Steroid hormones and vitamin D are synthesized from cholesterol
or a related sterol in a series of hydroxylations catalyzed by
enzymes of the cytochrome P-450 family, all of which have a critical
heme group (its absorption at 450 nm gives this family its name).

• In the hydroxylation reactions, one atom of molecular oxygen is

incorporated into the substrate and the second is reduced to H2O
• Another large family of P-450 enzymes is found in the
ER of hepatocytes.
• These enzymes catalyze reactions similar to the
mitochondrial P-450 reactions, but their substrates
include a wide variety of hydrophobic compounds,
many of which are xenobiotics—compounds not found
in nature but synthesized industrially.
• The P-450 enzymes of the ER have very broad and
overlapping substrate specificities.
• Hydroxylation of the hydrophobic compounds
makes them more water soluble, and they can
then be cleared by the kidneys and excreted in
urine.
• Among the substrates for these P-450 oxygenases
are many commonly used prescription drugs.
Metabolism by P-450 enzymes limits the drugs’
lifetime in the bloodstream and their therapeutic
effects.
• The biosynthesis of sphingolipids
takes place in four stages:
• A) synthesis of the 18-carbon
amine sphinganine from
palmitoyl-CoA and serine;
• B) attachment of a fatty acid in
amide linkage to yield N-
acylsphinganine;
• C) desaturation of the
sphinganine moiety to form
acylsphingosine (ceramide);
• D) attachment of a head group
to produce a sphingolipid such
as a cerebroside or
sphingomyelin
Condensation of palmitoyl-CoA and

serine followed by reduction with

NADPH yields sphinganine,

which is then acylated to N-

acylsphinganine

(a ceramide).
Biosynthesis of gangliosides. (NeuAc, N-
acetylneuraminic acid.)
Polar Lipids Are Targeted to Specific Cellular Membranes

• Membrane lipids are insoluble in water, so they cannot simply

diffuse from their point of synthesis (the ER) to their point of
insertion. Instead, they are delivered in membrane vesicles that bud
from the Golgi complex then move to and fuse with the target
membrane.

• Cytosolic proteins also bind phospholipids and sterols and transport

them between cellular membranes. These mechanisms contribute
to the establishment of the characteristic lipid compositions of
organelle membranes.
• Sphingolipids are normally digested in lysosomes. The
sugars are removed from the terminal ends of the
oligosaccharide by lysosomal exoglycosidases, and a
deficiency of any of these enzymes blocks the removal
of any of the remaining sugars.

• Several genetic diseases referred to as sphingolipidoses

result from deficiencies in these lysosomal enzymes
 • Sphingomyelin is degraded
by sphingomyelinase, a
lysosomal enzyme that
hydrolytically removes
phoshorylcholine , leaving
a ceramide .
• The ceramide is , in turn,
cleaved by ceramidase into
sphingosine and a free
fatty acid

Accumulation o f lipids in spleen

cells from a patient with Niemann-Pick disease .
• RELATED DISEASES OF FATTY ACID METABOLISM

• Medium-Chain Acyl-Coenzyme A Dehydrogenase

Deficiency
• Long-chain fatty acids are oxidized until reaching
a chain length of about 16 carbons. Because of
the inability to use fatty acids to support
gluconeogenesis, this deficiency produces a
nonketotic hypoglycemia. It is normally
dangerous only in cases of extreme or frequent
fasting.
• Jamaican Vomiting Sickness
• The unripe fruit of the Jamaican ackee tree
contains a toxin, hypoglycin, that inhibits both
the medium- and short-chain acyl-CoA
dehydrogenases. This inhibits b-oxidation and
leads to nonketotic hypoglycemia.
• Zellweger Syndrome
• Associated with the absence of peroxisomes in
the liver and kidneys, Zellweger syndrome
results in accumulation of very long chain fatty
acids, especially in the brain.
• Carnitine Deficiency
• Carnitine deficiency produces muscle aches and
weakness following exercise, elevated blood FFAs,
and low fasting ketone production. Nonketotic
hypoglycemia results because gluconeogenesis
cannot be supported by fat oxidation.
• Refsum Disease
• Also referred to as deficienta-oxidation, Refsum
disease results in accumulation of phytanic acid
in the brain, producing neurologic symptoms.
Phytanic acid is a branched-chain fatty acid found
in plants and in dairy products.