21| Lipid Biosynthesis

2013 W. H. Freeman and Company

 CHAPTER 21
Lipid Biosynthesis

Key topics:
Biosynthesis of fatty acids and eicosanoids
Assembly of fatty acids and glycerol into
triacylglycerols
Biosynthesis of cholesterol
 Lipids
fulfill a variety of biological
functions
Energy storage
Constituents of membranes
Anchors for membrane proteins
Cofactors for enzymes
Signaling molecules
Pigments
Detergents
Transporters
Antioxidants
 Catabolism and anabolism of
fatty acids proceed via different
pathways
Catabolism of fatty acids
produces acetyl-CoA
produces reducing power (NADH)
takes place in the mitochondria

Anabolism of fatty acids

requires acetyl-CoA and malonyl-CoA
requires reducing power from NADPH
takes place in cytosol in animals, (chloroplast in
plants)
 21.1 Biosynthesis of fatty acids and
Eicosanoids
- Fatty acid biosynthesis and breakdown occur by different pathways,
are catalyzed by different sets of enzymes,
and take place in different parts of cell
- The biosynthesis requires the participation of a three-carbon intermediate,
malonyl CoA

Malonyl-CoA is formed from acetyl-CoA and bicarbonate

- The formation of malonyl-CoA from acetyl-CoA is an irreversible process
catalyzed by acetyl-CoA carboxylase, containing biotin prosthetic group
(Fig21-1)
 Malonyl-CoA is formed
from acetyl-CoA and bicarbonate
Rx carboxylates acetyl CoA
Catalyzed by acetyl-CoA carboxylase
Enz has three subunits:
One unit has Biotin covalently linked to Lys
Biotin carries CO2
In animals, all three subunits are on one
polypeptide chain
HCO3 (bicarbonate) is the source of CO 2
The Acetyl-CoA
Carboxylase
Reaction
Acetyl-CoA carboxylase
has three functional regions:
biotin carrier protein (gray);
biotin carboxylase,
and transcarboxylase,
which transfers activated CO2
(shaded green)
from biotin to acetyl-CoA,
producing malonyl-CoA.

The long, flexible biotin arm

carries the activated CO2 from
the biotin carboxylase region to
the transcarboxylase active site.

The active enzyme in each step

is shaded in blue.
 Fatty Acid Synthesis
Overall goal: attach two-C acetate unit from malonyl-
CoA
to a growing chain and then reduce it
Reaction involves cycles of four enzyme-catalyzed steps
- Condensation of the growing chain with activated
acetate
- Reduction of carbonyl to hydroxyl
- Dehydration of alcohol to trans-alkene
- Reduction of alkene to alkane
The growing chain is initially attached to the enzyme
via a thioester linkage
During condensation, the growing chain
is transferred to the acyl carrier protein
After the second reduction step, the elongated chain
is transferred back to fatty acid synthase
 Synthesis of fatty acids
is catalyzed
by fatty acid synthase (FAS)

catalyzes a repeating four-step

sequence that elongates the fatty acyl
chain by two carbons at each step
See Fig. 21-2
Uses NADPH
as the electron donor
Uses two enzyme-bound -SH
groups
as activating groups

FAS I in vertebrates and fungi

FAS II in plants and bacteria
 FAS I vs. FAS II

FAS I FAS II
Single polypeptide Made of separate,
chain diffusible enzymes
in Makes many products
vertebrates (saturated,
Leads to single unsaturated,
product: branched, many
palmitate 16:0 lengths, etc.)
C-15 and C-16 are from Mostly in plants and
the acetyl CoA used to bacteria
prime the Rx
The structure of fatty acid synthase type I systems.

(a)All of the active sites in the mammalian system

are located in different domains within a single large polypeptide chain.

The 7 different enzymatic activites are:

-ketoacyl-ACP synthase (KS),
malonyl/acetyl-CoAACP transferase (MAT),
-hydroxyacyl-ACP dehydratase (DH), enoyl-ACP reductase (ER),
and -ketoacyl-ACP reductase (KR).

ACP is the acyl carrier protein.

The linear arrangement of the domains in the polypeptide
is shown in the lower panel.
The seventh domain (TE) is a thioesterase that releases the palmitate product
from ACP when the synthesis is completed.

*The ACP and TE domains are disordered in the crystal

and are therefore not shown in the structure.
 Enzymes in Fatty Acid
Synthase
Condensation with acetate
-ketoacyl-ACP synthase (KS)
Reduction of carbonyl to hydroxyl
-ketoacyl-ACP reductase (KR)
Dehydration of alcohol to alkene
-hydroxyacyl-ACP dehydratase (DH)
Reduction of alkene to alkane
enoyl-ACP reductase (ER)
Chain transfer/charging
Malonyl/acetyl-CoA ACP transferase
Fatty Acid Synthase Type I
Systems
Overall Palmitate
Synthesis
The overall process of palmitate synthesis.

- The fatty acyl chain grows by two-carbon units donated

by activated malonate, with loss of CO2 at each step.

- The initial acetyl group is shaded yellow, C-1 and C-2 of

malonate are shaded light red, and the carbon released
as CO2 is shaded green.
- After each two-carbon addition, reductions convert
the growing chain to a saturated fatty acid of four,
then six, then eight carbons, and so on.
The final product is palmitate (16:0).

The synthase stop generally at this point. dont

why!!!
 Acyl Carrier Protein (ACP)
serves as a shuttle in fatty acid
synthesis
contains a covalently
attached prosthetic group,
4-phosphopantetheine

- Flexible arm to tether acyl

chain
while carrying intermediates

from one enzyme subunit to

the next

Delivers acetate (in the first

step) or malonate (in all the
next steps) to the fatty acid
synthase
 Charging ACP and FAS I
with acyl groups activates them
Two thiols must be charged with the correct
acyl groups before condensation rx can begin
Thiol from 4-phosphopantethine in ACP
Thiol from Cys in fatty acid synthase
1)Acetyl group of acetyl-CoA is transferred to ACP
Catalyzed by malonyl/aceyl-CoA transferase (MAT)
ACP passes this acetate to the Cys of the -ketoacyl-ACP
synthase (KS) domain of FAS 1

2) ACP SH group is re-charged with malonyl from

malonyl-CoA
Charging, Activation
with ACP, and the
Four-Step Sequence
of Mammalian Fatty
Acid Synthesis
 Fatty Acid Synthesis in Detail:
Step 1:Condensation

Activated acetyl and malonyl groups

form acetoacetyl-ACP and CO2
Claisen condensation rx
Catalyzed by -ketoacyl-ACP synthase
Coupling condensation to
decarboxylation of malonyl-CoA makes
the rx energetically favorable
 Fatty Acid Synthesis in
Detail:
Step 2: Reduction

Carbonyl at C-3 is reduced

to form D--hydroxybutyryl-
ACP
- NADPH is e donor

Catalyzed by
-ketoacyl-ACP reductase
(KR)
 Fatty Acid Synthesis in Detail:
Step 3: Dehydration

OH and H removed from C-2 and C-3

of -hydroxybutyryl-ACP
to form trans-2-butenoyl-ACP

Catalyzed by
-hydroxyacyl-ACP dehydratase
(DH)
 Fatty Acid Synthesis in Detail:
Step 4: Reduction (2nd)

NADPH is the electron donor to reduce

double bond of trans-2-butenoyl-ACP
to form butyryl-ACP

Catalyzed by
enoyl-ACP reductase (ER)
 The Transferase and FAS
rxs are repeated in new
rounds
Product of first round is butyryl-ACP
(bound to phosphopantetheine-SH group
of ACP)
Butyrul gp is transferred to the Cys
of -ketoacyl-ACP synthase
In the first round, acetyl-CoA was bound
here
New malonyl-CoA binds to ACP
After new round of four steps,
six-C product is made (bound to ACP)
 The fatty acid synthase reaction
are repeated to form
palmitate
- Production of the four-carbon, saturated fatty-acyl-ACP marks
completion of one pass through the fatty acid synthase complex

- To start the next cycle of four reactions that lengthens the chain
by two more carbons, another malonyl group is linked to
the new unoccupied phosphopantetheins SH group of ACP
(Fig 21-
7)

- Seven cycles of condensation and reduction

produce the16-carbon saturated palmitoyl group.

The synthase stop generally at this point.

Beginning of
the Second
Round of Fatty
Acid Synthesis
 Stoichiometry of
Synthesis of Palmitate (16:0)
1) 7 acetyl-CoAs are carboxylated to make 7 malonyl-CoAs
using ATP

7 AcCoA + 7 CO2 + 7 ATP 7 malCoA + 7 ADP + 7 Pi

2) Seven cycles of condensation, reduction, dehydration and

reductionusing NADPH to reduce the -keto group and
trans-double bond

AcCoA + 7 malCoA + 14 NADPH + 14 H +

Palmitate + 7 CO2 + 8 CoA + 14
NADP+ + 6 H2O

(eq. 21-3)
Note: Eukaryotes have one additional energy cost. (Next
slide)
 Compartmentalization of Lipid
Metabolism in Animal Cells vs.
Plant Cells

Fatty acid synthesis takes place in the compartment

in which NADPH is available for reductive synthesis;
this is the cytosol in animals and yeast, and the chloroplast in
 Acetyl-CoA is transported into
the cytosol for fatty acid
synthesis
In nonphotosynthetic eukaryotes
Acetyl-CoA is made in the mitochondria
But fatty acids are made in the cytosol
So, Acetyl-CoA is transported
into the cytosol with a cost
of 2 ATPs
Therefore,
The cost of FA synthesis is 3 ATPs per 2-C
unit
 Fatty acid synthesis occurs in cell
compartments where NADPH levels
are high
Cytosol for animals, yeast
Chloroplast for plants

Sources of NADPH:
In adipocytes:
pentose phosphate pathway and malic enzyme (Fig.
21-9)
NADPH made as malate converts to pyruvate + CO2
In hepatocytes and mammary gland:
pentose phosphate pathway
NADPH made as glucose-6-phosphate converts
to ribulose 6-
phosphate
In plants: photosynthesis
Pathways for NADPH Production
 Acetate is shuttled out of mitochondria
as citrate (1)

- All the acetyl CoA used in fatty acid synthesis

is formed in mitochondria from pyruvate oxidation
and from catabolism of the carbon skeletons of
amino acids

- The mitochondria inner membrane

is impermeable to
acetyl-CoA,
so, indirect shuttle transfers
acetyl group equivalents across the inner
membrane
 Acetyl-CoA, generated in the
mitochondria, is shuttled to the
cytosol as citrate (2)
In most eukaryotes,
the acetyl-CoA for lipid synthesis
is made in the mitochondria
But lipid synthesis occurs in the cytosol
And there is no way for acetyl-CoA to cross
mitochondrial inner membrane to the cytosol

So acetyl-CoA is converted to citrate

Acetyl-CoA + oxaloacetate citrate
Same rx as occurs in CAC
Catalyzed by citrate synthase
Citrate passes through citrate transporter
 Oxaloacetatecyt is converted to
malate (3)
Malate dehydrogenase in cytosol
reduces oxaloacetate to malate
Two potential fates for malate:
can be converted to NADPHcyt and pyruvatecyt
via the malic enzyme
NADPH used for lipid synthesis
Pyruvatecyt sent back to mt via pyruvate transporter
Converted back to oxaloacetatemt by pyruvate carboxylase,
requires ATP
can be transported back
to mt via malate --ketoglutarate transporter
Malatemt is reoxidized to oxaloacetatemt
 Shuttle for transfer of acetyl groups
from mitochondria to the cytosol.

The outer mitochondrial membrane

is freely permeable to all these compounds.
Pyruvate derived from amino acid catabolism in the mitochondrial matrix, or from
glucose by glycolysis in the cytosol, is converted to acetyl-CoA in the matrix.
Acetyl groups pass out of the mitochondrion as citrate; in the cytosol they are
delivered as acetyl-CoA for fatty acid synthesis.
Oxaloacetate is reduced to malate, which can return to the mitochondrial matrix and
is converted to oxaloacetate.
The major fate for cytosolic malate is oxidation by malic enzyme to generate
cytosolic NADPH; the pyruvate produced returns to the mitochondrial matrix.
Shuttle for Transfer of Acetyl Groups
from Mitochondria to Cytosol
 Fatty acid synthesis
is tightly regulated via ACC

Acetyl CoA carboxylase (ACC)

catalyzes the rate-limiting step
- ACC is feedback-inhibited by palmitoyl-CoA
- ACC is activated by citrate
Remember citrate is made from acetyl-CoA mt
Citrate signals excess energy
to be converted to
fat
- When [acetyl-CoA]mt ,
converted to citratecitrate exported to
cytosol
 Regulation of Fatty Acid
Synthesis
in Vertebrates
Both allosteric regulation
and hormone-dependent
covalent modification
influence
the flow of precursors
into malonyl-CoA.
Long-chain saturated
fatty acid are synthesized
from palmitate

- Palmitate,
the principal
product of the fatty
acid
synthase in animal
cell,

is the precursor of
other
long-chain fatty acid
(Fig 21-12)
(p842)
 Desaturation of a Fatty Acid
by Fatty Acyl-CoA desaturase
. Blue arrows show the path of electrons as two substrates
a fatty acylCoA and NADPHundergo oxidation by O2.
 fatty acyl desaturase
is a non-heme, iron-containing, mixed
function oxidase

O2 accepts four electrons from two substrates

Two electrons
come from saturated fatty acid
Two electrons
come from ferrous state of
cytochrome b5
 Eicosanoids are formed
from 20-carbon
polyunsaturated fatty acid

- Eicosanoids are a family of very potent biological

signaling molecules
that act as short-range messengers,
affecting tissue near the cells
that produce them (Fig 21-15, 16) (p845)
Eicosanoids are potent short-range
hormones made from arachidonate
Eicosanoid hormones
include prostaglandins, leukotrienes,
thromboxanes

created from the arachidonate 20:4 thats incorporated

into the phospholipids of membranes

In response to stimuli (hormone, etc.),

phospholipase A2 is activated and attacks the
C-2
fatty acid, releasing arachidonate
 Conversion of
Arachidonate
to
Prostaglandin
s and Other
Eicosanoids
After arachidonate is released
from phospholipids by the action
of phospholipase A2,

the cyclooxygenase and peroxidase

activities of COX (also called
prostaglandin H2 synthase) catalyze
the production of PGH2,
the precursor of other prostaglandins
and thromboxanes.
 NSAIDs inhibit
cyclooxygenase activity
See Fig. 21-15b
Aspirin (Acetylsalicylate)
is an irreversible inhibitor
- acetylates a Ser in active site
- blocks active site in both COX isozymes
Ibuprofen and Naproxen
are competitive inhibitors
- resemble substrate,
also block active site in both isozymes
 A Few NSAIDs that Inhibit PGH2

Aspirin
- inhibits the first reaction
by acetylating an essential
Ser residue on the enzyme.

Ibuprofen and naproxen

- inhibit the same step,
probably by mimicking
the structure of the substrate
or
an intermediate in the reaction.
 Leukotriene synthesis
also begins with
arachidonate

O2 is added to arachidonate
via lipoxygenases (mixed-function
oxidases)
creates species
that differ in the position of the
OOH group
See Fig. 21-16
Synthesis of Leukotrienes
21.2 Biosynthesis of
Triacylglycerol
Triacylglycerols and glycerophospholipids
are synthesized from the
same precursors
Glycogen can be stored only a few hundred grams in liver and muscle,
~12 hr using.

Triacyglycerol can be stored ~20kg, supporting for 12 weeks.

In animal tissue,
triacyglycerol and glycerophospholipid
share two precursor (fatty acyl-CoA and L-glycerol 3-phosphate)
and several steps.
(Fig 12-17, 18)
 Synthesis of
Phosphatidic
Acid
- A fatty acyl group
is activated
by formation of the fatty acyl
CoA, then transferred to ester
linkage with L-glycerol 3- phosphate,

- Phosphatidic acid is shown here

with the correct stereochemistry
at C-2 of the glycerol molecule
Conversion of
Phosphatidic
Acid
into
Triacylglycerol
- Phosphatidic acid
is the precursor of both
triacylglycerols
and
glycerophospholipids.
Triacylglycerol biosynthesis in
animal
is
regulated by hormone

- Insulin promotes
the conversion of carbohydrate to
triacylglycerol

(Fig 21-19)
Severe diabetes mellitus make people
to fail to synthesize fatty acid from carbohydrate or
amino acid

- Glucagon and epinephrine

 Regulation of Triacylglycerol
Synthesis
by Insulin
- Insulin
stimulates conversion of dietary
carbohydrates and proteins to fat.
( Individuals with diabetes
mellitus either lack insulin
or are insensitive to it. )

- This results in diminished fatty

acid synthesis, and the acetyl-
CoA arising from catabolism
of carbohydrates and proteins
is shunted instead to
ketone body production.

* People in severe ketosis smell

of acetone, so the condition
is sometimes mistaken
for drunkenness
 Triacylglycerol breakdown and
re-synthesis create a futile cycle
75% of free fatty acids (FFA) released by lipolysis
are reesterified to form TAGs rather than be
used for fuel

Some recycling occurs in adipose tissue

Some FFA from adipose cells are transported to liver,
remade into TAG, and re-deposited in adipose cells
 The triacylglycerol cycle.

In mammals, triacylglycerol molecules are broken down and

resynthesized in a triacylglycerol cycle during starvation.
Some of the fatty acids released by lipolysis of triacylglycerol
in adipose tissue pass into the bloodstream, and the remainder
are used for resynthesis of triacylglycerol.
Some of the fatty acids released into the blood are used for
energy (in muscle, for example), and some are taken up by the
liver and used in triacylglycerol synthesis.
The triacylglycerol formed in the liver is transported in the
blood back to adipose tissue, where the fatty acid is released
by extracellular lipoprotein lipase, taken up by adipocytes,
and reesterified into triacylglycerol.
The Triacylglycerol Cycle
 Benefits of this futile cycle?
Recycling continues even in starvation
Speculation:
energy reserve for fight or flight crises
that might occur during fasting

The total # of FFA in flux may change but the

% recycled remains
unless a pharmacological intervention
happens
(i.e., thiazolidinedione drugs)
Adipose tissue generates
glycerol 3-phosphate by
glyceroneogenesis

(p850)
- glyceroneogenesis
is a shortened version of gluconeogenesis,
from pyruvate to DHAP, followed by conversion
of the DHAP to glycerol 3-phosphate (Fig 21-21)

- Cortisol and Dexamethasone hormone

- stimulate glyceroneogenesis
and gluconeogenesis in the liver,
- suppressing glyceroneogenesis
in the adipose tissue (Fig 21-22)
 Glyceroneogen
esis
The pathway is essentially
an abbreviated version
of gluconeogenesis,
from pyruvate to dihydroxyacetone
phosphate (DHAP),

followed by conversion of DHAP

to glycerol 3-phosphate, which is
used for the synthesis
of triacylglycerol.
 What is the source
of the glycerol 3-phosphate
needed for fatty acid re-
esterification?
During lipolysis (stimulated by glucagon or epinephrine) ,

glycolysis is inhibited
So DHAP is not readily available
to make glycerol 3-phosphate

And adipose cells dont have glycerol kinase

to make glycerol 3-phosphate on-site

So, cells make DHAP via glyceroneogenesis

See next slide
 Regulation of
Glyceroneogenesis
via Glucocorticoid
Hormones
Glucocorticoid hormones stimulate
glyceroneogenesis and gluconeogenesis in the
liver,
while suppressing glyceroneogenesis in the
adipose tissue (by reciprocal regulation of the
gene expressing PEP carboxykinase (PEPCK) in
the two tissues);
this increases the flux through the
triacylglycerol cycle. The glycerol freed by the
breakdown of triacylglycerol in adipose tissue
is released to the blood and transported to the
liver,
Regulation of Glyceroneogenesis
via Glucocorticoid Hormones
 Regulation of
Glyceroneogenesis
via Thiazolidinediones
A class of drugs called thiazolidinediones
are now used to treat type 2 diabetes.
In this disease, high levels of free fatty acids in the
blood interfere with glucose utilization in muscle
and promote insulin resistance.
Thiazolidinediones activate a nuclear receptor
called peroxisome proliferator-activated
receptor (PPAR),
which induces the activity of PEP
carboxykinase.
Therapeutically, thiazolidinediones increase the
rate of glyceroneogenesis,
 Regulation of
Glyceroneogenesis
via Thiazolidinediones
Thiazolidinedione drugs target
insulin resistance
by increasing
Elevated FFA levels
glyceroneogenesis seem to promote insulin resistance

Thiazolidinediones (glitazones)
upregulate PEPCK in adipose tissue,
lead to glyceroneogenesis,
resynthesis of TAG in adipose tissue
and release of FFA

Thus the drugs promote sensitivity to insulin

 Thiazolidinediones

Avandia (Rosiglitazone) removed from

Have this group
market due to association with heart at
in common

Pioglitazone (Actos)
21.3 Biosynthesis of membrane
phospholipids
Two major classes of membrane phospholipids:
(p852)
glycerophospholipids and sphingolipids

All the biosynthetic pathways follow a few basic

patterns.
(1) synthesis of backbone molecule (glycerol or sphingosine)
(2) attachment of fatty acid to the backbone
through as ester or amide linkage
(3) addition of a hydrophilic head group to the backbone
through a phosphodiester linkage, in some
case
(4) alternation or exchange of the head group
to yield the final phospholipid product
 Attachment of Head Group
to Diacylglycerol

- The phospholipid head group

is attached to a diacylglycerol
by a phosphodiester bond,
formed when phosphoric acid
condenses with two alcohols,
eliminating two molecules of H2O.
 Forming the Phosphodiester
Bond
of the Head Group

Either one of the alcohols

is activated by attaching to CDP (cytidine
diphosphate)

The free (not bound to CDP) alcohol

then does nucleophilic attack on the CDP-activated
phosphate

Releases CMP and a glycerophospholipid

See Fig. 21-24
 Forming the Phosphodiester
Bond
of the Head Group
Cells
have two strategies

for attaching
phospholipid head
groups
- CDP is used as
activating group
(Fig 21-24)
 Phospholipid synthesis in E Coli
employs CDP-diacylglycerol
- Phosphatidylserine, phosphatidylethanolamine,
phosphatidylglycerol
(Fig
21-25)

***Eukaryotes synthesize
anionic phosphoslipids from CDP-diacylglycerol
- phosphatidylglycerol, cardiolipin, and
phosphatidylinocitols

(Fig 21-26)
 Phospholipid Synthesis in E. coli
employs CDP-diacylglycerol (Fig 21-
25)

- Initially, a head group

(either serine or glycerol 3-phosphate)
is attached
via a CDP-diacylglycerol intermediate
(strategy 1 in Fig. 2124).

- For phospholipids other than

phosphatidylserine,
the head group is further modified,
as shown here.

In the enzyme names,

PG represents phosphatidylglycerol;
PS, phosphatidylserine.
 Synthesis of Anionic Lipids
Cardiolipin and Phosphatidylinositol in
Eukaryotes

Cardiolipin
a phospholipid
existing in heart
and mitochondria
 Synthesis of Phosphatidylethanolamine
and Phosphatidylcholine in all
eukaryotes (Fig 21-27)
The major path
from phosphatidylserine
to phosphatidylethanolamine
and
phosphatidylcholine
in all eukaryotes.

AdoMet
is S-adenosylmethionine;

adoHcy,
is S-adenosylhomocysteine.
Phosphatidic acid is formed by transacylation of
L-glycerol 3-phosphate with fatty acyl groups
donated from fatty acyl-CoA.
Summary of the pathway
for synthesis of major phospholipids and triacylglyceroles
Pathways for phosphatidylserine synthesis in mammals (a)

A salvage pathway
using
serine or ethanolamine

PSS1; Phosphatidylserine synthase 1

Pathways for
phosphatidylcholine synthesis
in mammals (b)

A salvage pathway
using choline
Synthesis of ether lipids and plasmalogens

Plasmogen, ether lipids,

involves the displacement
of an esterified fatty acyl group
by a long-chain alcohol
to form the ether linkage
Sphigolipid and glycerophospholipid synthesis
share precursors and some
mechanisms

- The biosynthesis of sphingolipid take place in four stages

(Fig 21-31)

Palmitoyl CoA + Serine + NADPH ---

(1) Sphinganine synthesis

(2) N-acylsphingasine
(3) N-acysphingosine
(4) cerebroside or sphigomyelin produce

Polar lipids are targeted to specific cellular membranes

- synthesis on the smooth ER

- are inserted into specific cellular memnrane
Biosynthesis of sphingolipids

Condensation
of palmitoyl CoA and serine
followed by reduction with
NADPH yields sphiganine,
which is then acylated to a
ceramide
then produce
a sphingolipid
such as
a cerebroside or sphigomyelin
21.4 Cholesterol, Steroids,
and Isoprenes
Topics:
Cholesterol synthesis
Cholesterol transport
Cholesterol uptake
Normal and defective regulation of cholesterol
synthesis, uptake and transport
Cholesterol derivatives (bile acids, steroid
hormones)
Synthesis of compounds derived from isoprene
21.4 Biosynthesis
of cholesterol,
steroids, isoprenoids

Cholesterol is important for human cardiovascular

disease,
a component
Cholesterol of cellular
is made from membranes,
acetyl-CoA in four
stages and as a precursor of steroid hormones and bile
acids
- is made from acetyl CoA (Fig 21-32)
- synthesized by four steps (Fig 21-33)

Acetate -> Mevalonate -> Squalene -> Cholesterol

(Fig 21-34, 35, 36, 37)
Origin of the carbon atoms of
cholesterol
Four Steps of Cholesterol
Synthesis
1) Three acetate
condense to form mevalonate
2) Mevalonate
converts to phosphorylated 5-C
isoprene
3) Six isoprene
polymerize to form the 30-C linear
squalene
4) Squalene
cyclizes to form the four rings
that are modified to produce
cholesterol
Cholesterol
Synthesis
The four stages
are discussed in the
above.

Isoprene units in squalene

are set off by red dashed
lines.
Step 1:
Formation of
Mevalonate
from Acetyl-
CoA

The origin of C-1 and

C-2 of mevalonate
from acetyl-CoA is
shaded light red.
 Step 2:
Conversion of
Mevalonate to
Activated
Isoprenes
Six of these activated units
combine to form squalene
(see Fig. 2136).
Formatio
n
of
Squalene
 Conversion
of Squalene
to Cholesterol
The first step in this sequence is
catalyzed by a mixed-function
oxidase (a monooxygenase),
for which the cosubstrate 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; in other organisms,
slightly different sterols are
produced, as shown.
 Cholesterol has several fates
(p864)
- synthesized in liver, exported in one of
three form:
biliary cholesterol, bile acids, cholesteryl
ester
- used as membrane synthesis,
steroid hormone precursor, vitamin D
precursor
Cholesterol and other lipids
(Fig 21-38, explain!!!)
are carried on plasma lipoproteins
- is insoluble in water,
- is carried in blood plasma
as plasma lipoprotein, apolipoprotein
(Fig 21-39)
- major classes of plasma protein (Table 21-1)
(Table 21-2)
- chylomicron, VLDL, LDL, HDL
Metabolic fates of cholesterol

Modification of the cholesterol

structure are shown in red.
Esterification converts cholesterol
to an even more hydrophobic form
for storage and transport
Metabolic fates of cholesterol
Lipoprotein
Electron Microscope Pictures of
Lipoproteins
chylomicrons, 50 to 200 nm in diameter; VLDL, 28 to 70 nm;
HDL, 8 to 11 nm; and LDL, 20 to 25 nm.
 Four Major Classes
of Lipoprotein Particles

Named based on position of sedimentation

(density) in centrifuge
Large enough to see in electron microscope (see
Fig. 21-39b; next slide).
Includes:
Chylomicrons (largest and least dense)
Very low-density lipoproteins (VLDL)
Low-density lipoproteins (LDL)
High-density lipoproteins (HDL) smallest, most
dense
 Apolipoproteins in
Lipoproteins
Apo for without
So apolipoprotein
refers to the protein part of a lipoprotein particle
Provide sites for the particle to bind to
cell surface receptors, activate enzymes,
etc.
At least ten have been characterized in
humans
See Table 21-2
Lipoproteins and lipid transport
 Lipoproteins and lipid transport
Lipids are transported in the
bloodstream as lipoproteins, which
exist as several variants that have
different functions, different
protein and lipid compositions and
thus different densities.
 LDLs carry cholesterol from
liver
to muscle and adipose tissue
Muscle and adipose tissue
have LDL receptors, recognize
apoB-100
See Fig. 21-41

Enable myocytes and adipocytes

to take up cholesterol
via receptor-mediated endocytosis
 Cholesterol esters enter cell by receptor
mediated endocytosis (Fig 21-41) (Fig 21-42)

Cholesterol biosynthesis is regulated at

several steps
(Fig 21-43) (Fig 21-44)
- is regulated by cholesterol concentration, glucagon, insulin
and HMG-CoA reductase

Atherosclerosis
- caused by unregulated cholesterol production in blood vessels
- high level of LDL-bound cholesterol; there is negative
correlation between HDL level
- caused heart failure & death
- In familial hypercholesterolemia, severe atherosclerosis develops
in childhood
 Cholesterol Uptake
by Receptor-Mediated
Endocytosis
 Lecithin-Cholesterol Acyl
Transferase (LCAT)
- Catalyzed Reaction
This enzyme
is present on the surface of HDL
and is stimulated by the HDL
component apoA-I.

Cholesteryl esters accumulate

within nascent HDLs, converting
them to mature HDLs.
 Five Modes of Regulation of
Cholesterol Synthesis and
Transport
1) Covalent modification of HMG-CoA reductase
2) Transcriptional regulation of HMG-CoA gene
3) Proteolytic degradation of HMG-CoA reductase
4) Activation of ACAT, which increases
esterification for storage
5) Transcriptional regulation of the LDL receptor
 HMG-CoA reductase
is most active when
dephosphorylated
1) AMP-dependent protein kinase
- when AMP rises,
kinase phosphorylates the enzyme
activity , cholesterol synthesis
2) Glucagon, epinephrine
- cascades lead to phosphorylation, activity
3) Insulin
- cascades lead to dephosphorylation,
activity
Covalent modification provides short-term regul
Regulation of
Cholesterol
Metabolism
Longer-term Regulation of HMG-CoA
Reductase
through Transcriptional Control
(Fig 21-44)

Sterol regulatory element-binding proteins

(SREBPs)
When sterol levels are low,
SREBP is in ER membrane with other
proteins
When sterol levels rise,
complex is cleaved, moves to the nucleus
activates transcription of HMG-CoA reductase
and LDL receptor as well as other genes
Regulation of Cholesterol
Synthesis by SREBP
 Steroid hormones
are formed by side-
chain cleavage
and oxidation of
cholesterol
- Human derive all their steroid hormones from
cholesterol
(Fig 21-45) (Fig 21-46)

Intermediates in cholesterol
biosynthesis
have many
alternative fates
 Regulation by LXR-
mediated Transcription

Liver X Receptor (LXR)

a transcription factor activated by
cholesterol
Binds to retinoid X receptor (RXR)
LXR-RXR dimer activates transcription
of a host
of genes
Action RXR-LXR dimer on expression of genes
for lipid and glucose metabolism
 Review of Cholesterol
Regulation
Insulin cascades
stimulate HMG-CoA reductase
Transcription
increases when cholesterol levels are
low
- SREBPs activated
Transcription
slows when cholesterol levels are high
- LXRs activated
 Cardiovascular disease
(CVD)
is multi-factorial
Very high LDL-cholesterol levels
tend to correlate with atherosclerosis
Although many heart attack victims
have normal cholesterol, and many people
with high cholesterol do not have heart attacks

Low HDL-cholesterol levels

are negatively associated with heart
disease
 Role of form cells
in formation of atherosclerotic
plaques
 How Plaques Form

LDL with partly oxidized fatty acyl groups

sticks to the lining of arteries.
- attracts macrophage cells
of the immune system.
These cells dont regulate their uptake of
sterols, so they accumulate cholesterol and
cholesteryl esters
The macrophages become foam cells
(named for appearance)
How Plaques Form (cont.)

Foam cells undergo apoptosis

Remnants accumulate,
along with scar tissue, etc.
can occlude a blood vessel or break off
and travel to another artery
Occlusion of blood vessels in the heart
cause heart attack; occlusion in the
brain causes stroke
 Familial
Hypercholesterolemia
Due to genetic mutation in LDL receptor
Impairs receptor-mediated uptake of
cholesterol from LDL
Cholesterol accumulates in the blood
and in foam cells
Regulation mechanisms based on
cholesterol sensing inside the cell dont
work
Homozygous individuals can experience
severe CVD as youths
 Statin drugs inhibit
HMG-CoA reductase to lower
cholesterol
Statins resemble mevalonate (p873)
competitive inhibitors of HMG-CoA reductase
First statin, lovastatin, found in fungi
lowers serum cholesterol by tens of percent

Side-effects
include muscle weakness, coenzyme Q depletion
Also reported to improve circulation, stabilize plaques
by removing cholesterol from them, reduce vascular
inflammation
 Reverse Cholesterol
Transport
Apo A-I and HDLs pick up
excess cholesterol from
peripheral cells, with the
participation of ABCA1 and
ABCG1 transporters, and
return it to the liver.

In individuals with genetically

defective ABCA1,
the failure of reverse
cholesterol transport leads to
severe and early cardiovascular
diseases:
Tangier disease and familial
HDL deficiency disease.
Reverse cholesterol transport by
HDL
explains why HDL is
cardioprotective (p873)
HDL picks up cholesterol
from non-liver tissues,
including foam cells at growing
plaques
ABC (ATP-Binding Cassette) transporters
bring cholesterol from inside the cell
to the plasma membrane
HDL carries cholesterol back to liver
 There are several classes
of cholesterol-derived
steroids
Adrenal gland-synthesized steroids:
Mineralocorticoids
Control electrolyte balance, reabsorption of
Na+, Cl, HCO3 from kidney
Glucocorticoids
Regulate gluconeogenesis, reduce
inflammation
Gonad-synthesized steroids:
Progesterone, androgens, estrogens
Steroid
Hormones
Derived from
Cholesterol
 How Steroids
Are Made from Cholesterol

Takes place in mitochondria

The side chain on C-17 of the D ring
is modified or
cleaved
Two adjacent carbons are hydroxylated
Uses mixed-function oxidases, NADPH
and
cytochrome P450
See Fig. 21-49
 Side-chain
Cleavage in
Steroid
-
Synthesis
Cytochrome P-450 acts as electron
carrier in this mixed-function oxidase
system that oxidizes adjacent carbons.

- The process also requires the electron-

transferring proteins adrenodoxin and
adrenodoxin reductase. This system
for cleaving side chains is found in
mitochondria of the adrenal cortex,
where active steroid production
occurs.

Pregnenolone is the precursor of all other

steroid hormones
(p875)
 Intermediates
in Cholesterol Synthesis

3-Isopentenyl pyrophosphate
can be made into over 20,000 additional
products

Includes Vitamins A, E, and D to plant hormones,

rubber, fragrant oils, quinone electron carriers,
and the phytol chain of chlorophyll, etc.

Usually involve prenylation

See Fig. 21-50
Synthesis of Isoprenoids;
Overview
Finish!!!
 Oxidases, Monooxygenases,
and Dioxygenases

Many enzymes use oxygen as an e acceptor,

but not all of them incorporate oxygen into the
product.
Oxidases do not incorporate oxygen into the
product
Oxygen atoms usually end up in H2O2
Oxygenases do incorporate oxygen into the product
Monooxygenases incorporate one of the oxygen
atoms into the product
Dioxygenases incorporate both oxygen atoms
into the product
 Monooxygenases
incorporate one oxygen into
the product
AH + BH2 + O-O A-OH + B + H2O
Product is often hydroxylated, so also called
hydroxylases or mixed-function oxygenases
Example: Phenylanine hydroxylase hydroxylates
phenylalanine to form tyrosine
Deficiency causes phenylketonuria
 Cytochrome P450s are
monooxygenases
Important in drug metabolism
Hydroxylate nonpolar molecules
usually inactivating them and making them
more H2O-solubile for excretion
If two drugs (or alcohol and a drug) use
the same P450, they will compete, and
levels of the drug or alcohol will not be
cleared as quickly
Can be deadly
 Dioxygenases incorporate
two oxygens in the product

Usually metalloproteins
Active sites have Fe or Mn ions
Rxs often involve opening an aromatic ring
Used to convert catechols to ketones
Example: Catechol 1,2-dioxygenase,
Tryptophan 2,3-dioxygenase (Next slide)
 Eicosanoids are potent
short-range hormones made
from arachidonate
Eicosanoid hormones include
prostaglandins, leukotrienes,
thromboxanes
Created from the arachidonate 20:4 thats
incorporated into the phospholipids of
membranes
In response to stimuli (hormone, etc.),
phospholipase A2 is activated and attacks
the C-2 fatty acid, releasing arachidonate
Prostaglandins are made by
prostaglandin H2 synthase
(PGH2)
PGH2 functions in the smooth ER.
Step 1: PGH2s cyclooxygenase
activity (COX), adds 2 O2 to form PGG2
Step 2: PGH2s peroxidase activity
converts peroxide to alcohol, creates
PGH2
PGH2 is precursor to other eicosanoids
See Fig. 21-15a
 PGH2 has two isoforms

COX-1 catalyzes synthesis of

prostaglandins that regulate gastric
mucin secretion
COX-2 catalyzes synthesis of
prostaglandins that mediate pain,
inflammation, and fever
NSAIDs (Aspirin, Ibuprofen, Acetaminophen)
inhibit COX-2
See Fig. 21-15b
 COX-2-specific inhibitors
have a checkered history
Developed to inhibit prostaglandin
formation without harming stomach
Includes Vioxx, Bextra, and Celebrex
See Fig. 21-15c
Vioxx and Bextra removed from market
due to increased rates of stroke and
heart attack
May disrupt balance between blood-thinning
prostacyclin and blood-clotting thromboxanes
 Fat (Triacylglycerol) and
Phospholipids in Animals,
Plants, and Bacteria
Animals and plants store fat for fuel
Plants: in seeds, nuts
Typical 70-kg human has ~15 kg fat
Enough to last 12 wks
Compare with 12 hrs worth glycogen in liver
and muscle
Animals and plants and bacteria make
phospholipids for cell membranes
The precursor for the backbone
of fat and phospholipids is
glycerol 3-phosphate

Most glycerol 3-phosphate comes from

siphoning off dihydroxyacetone
phosphate (DHAP) from glycolysis
via glycerol 3-phosphate dehydrogenase

Some glycerol 3-phosphate made from

glycerol
Via glycerol kinase
Minor pathway in liver and kidney
 Acyl transferases attach two
fatty acids to glycerol 3-
phosphate
Phosphatidic acid is the precursor to TAGs
and phospholipids
Made of glycerol 3-phosphate + 2 fatty acids
Fatty acids are attached by acyl transferases
Releases CoA
See Fig. 21-17

Advantage of making phosphatidic acid:

It can then be made into triacylglycerol OR
phospholipid
 To make TAG, phosphatidic
acid is dephosphorylated
and acylated
Phosphatidic acid phosphatase
(lipin) removes the 3-phosphate
from the phosphatidic acid
Yields 1,2-diacylglycerol
Third carbon is then acylated with
a third fatty acid
Yields triacylglycerol
See Fig. 21-18
 Regulation of
Triacylglycerol Synthesis
by Insulin
Insulin results in stimulation of
triacylglycerol synthesis
Lack of insulin results in:
Increased lipolysis
Increased fatty acid oxidation
Sometimes to ketones if citric acid cycle
intermediates (oxaloacetate) that react with
acetyl CoA are depleted
Failure to synthesize fatty acids
 Regulation of Fat
Metabolism by Glucagon
and Epinephrine
Glucagon and epinephrine result in
stimulation of triacylglycerol
breakdown (mobilization of fatty
acids)
Also decrease glycolysis
Also increase gluconeogenesis
 Regulation of PEPCK
expression is tissue-
dependent
Cortisol and glucagon both increase PEPCK
expression in liver.
Results in more TAG synthesis, so more released
to the blood
Cortisol and other glucocorticoids decrease
PEPCK expression in adipose tissue
glyceroneogenesis in adipose means less
recycling; more FFA are released into the blood
Most glycerol freed from TAG in adipose is sent
to liver and converted to glucose
 Cortisol and glucagon can
elevate blood sugar
PEPCK expression in liver
gluconeogenesis (so [glucose])

PEPCK expression in adipose tissue

glycerol freed, sent to liver, converted to
glucose

3) Plus, the FFA associated with increased flux

through TAG cycle interfere with glucose
uptake in muscle, keep [glucose]blood high
CDP-diacylglycerol is a precursor
to phosphatidylserine and
derivatives in E. coli
See Fig. 21-25
CDP-diacylglycerol is attacked by the
nucleophilic OH of serine
phosphatidylserine (and CMP)
Catalyzed by PS synthase
Phosphatidylserine is decarboxylated
Phosphatidylethanolamine
Catalyzed by PS decarboxylase
 CDP-diacylglycerol is also a
precursor to cardiolipin in E.
coli
See Fig. 21-25
CDP-diacylglycerols activated phosphate is
attacked by glycerol 3-phosphate
Phosphatidylglycerol 3-phosphate (and CMP)
Catalyzed by PG3-phosphate synthase
PG 3-phosphate is hydrolyzed PGglycerol
Catalyzed by PG3-phosphate phosphatase
Phosphatidylglycerol dimerizes to cardiolipin
Catalyzed by cardiolipin synthase
Synthesis of anionic phospholipids
in eukaryotes uses similar
strategies to that of E. coli

Phosphatidylinositol made from

CDP-diacylglycerol and inositol
Specific kinases make phosphorylated
derivatives
Difference from bacteria:
Cardiolipin made from attack of
phosphatidylglycerol on CDP-diacylglycerol
rather than from two
phosphatidylglycerols
 Synthesis of
Phosphatidylethanolamine and
Phosphatidylcholine in Yeast
See Fig. 21-27
Phosphatidylserine is decarboxylated to
phosphatidylethanolamine
(as in bacteria, but enz is phosphatidylserine
decarboxylase)
Phosphatidylethanolamine acted on by S-
adenosylmethione (methyl group donor),
adds three methyl groups to amino group
phopshatidylcholine (lecithin)
Catalyzed by methyltransferase
 Phospholipid Synthesis in
Mammals
Phosphatidylserine isnt synthesized from
CDP-diacylglycerol as it is in yeast and
bacteria
See Fig. 21-29a
Made backwards from
phosphatidylethanolamine or
phosphatidylcholine via head group
exchange rxs
Catalyzed by specific synthases
Pathway salvages the choline
Synthesis of Phosphatidylserine
and Phosphatidylcholine in
Mammals
Synthesis of Phosphtidylcholine in
Mammals by Another Pathway
 Formation of
Plasmalogens and Other
Ether Lipids
Ether linkage is made by displacing
an esterified fatty acid with a long-
chain alcohol
Attachment of head groups is
similar to the pathways for ester-
linked phospholipids
Fig. 21-30 in the text summarizes
these pathways
Sphingolipids are made in four
steps

1) Synthesis of sphinganine from palmitoyl-

CoA and serine
2) Attachment of fatty acid via amide
linkage
3) Desaturation of sphinganine
Yields N-acylsphingosine (ceramide)
4) Attachment of head group
Can yield a cerebroside or ganglioside

See Fig. 21-31 in text for detailed pathways

 Phospholipids must be
transported from the ER to
membranes
Phospholipids are:
synthesized in the smooth ER
transported to Golgi complex for additional synthesis
Must be inserted into specific membranes
in specific proportions but cant diffuse
because they are nonpolar
So transported in membrane vesicles that fuse
with target membrane
Details of the process are not well-understood
 Step 1: Formation of
Mevalonate from Acetyl-CoA
2 Acetyl-CoAs Acetyoacetyl-CoA
Catalyzed by acetyl-CoA acyl transferase
Acetyl-CoA + Acetoacetyl-CoA -hydroxyl-
-methylglutaryl-CoA (HMG-CoA)
Catalyzed by HMG-CoA synthase
NOT the mitochondrial HMG-CoA synthase used in ketone
body formation

HMG-CoA + 2 NADPH mevalonate

Catalyzed by HMG-CoA reductase
Rate-limiting step and point of regulation!
 Formation of Mevalonate
HMG-CoA reductase is a target for some
cardiovascular drugs
 Step 2: Conversion of
Mevalonate to Two Activated
Isoprenes
3 PO43 transferred stepwise from ATP to
mevalonate
Decarboxylation and hydrolysis creates a
diphosphorylated 5-C product
(isoprene) with a double bond
Isomerization to a second isoprene
The two activated isoprene units are
3-isopentyl pyrophosphate and
dimethylallylpyrophosphate
 Step 3: Six Activated
Isoprene Units Condense to
Form Squalene
The two isoprenes join head-to-tail,
displacing one set of diphosphates
forms geranyl pyrophopshate
Geranyl pyrophosphate joins to another
isopentenyl pyrophosphate
forms 15-C farnesyl pyrophosphate
Two farnesyl pyrophosphates join head-
to-head to form phosphate-free
squalene
 Step 4: Conversion of
Squalene to Four-Ring
Steroid Nucleus
Squalene monooxygenase adds one
oxygen to the end of the squalene chain
forms squalene 2,3-epoxide
Here pathways diverse in animal cells vs.
plant cells
The cyclization product in animals is
lanosterol, which converts to cholesterol
In plants, the epoxide cyclizes to other
sterols such as ergosterol
 Bile Acids Assist in
Emulsification of Fats

Bile is stored in the gall bladder,

secreted into small intestine after
fatty meal
Bile acids such as taurocholic acid
(see Fig. 21-23) emulsify fats
Surround droplets of fat, increase
surface area for attack by lipases
 Cholsteryl esters are
more nonpolar than
cholesterol
Contain a fatty acid esterified to
the oxygen (see Fig. 21-38)
Comes from a fatty acyl-CoA
Makes the cholesterol more
hydrophobic, unable to enter
membranes
Transported in lipoproteins to other
tissues or stored in liver
 Cholesterol and other
lipids are carried on
lipoprotein particles
Lipids are carried through the
plasma on spherical particles
Surface is made of protein (called
apolipoprotein) and a phospholipid
monolayer
Interior contains cholesterol, TAGs,
cholesteryl esters
See Fig. 21-39a (next slide)
 Chylomicrons carry fatty
acids to tissues

Have more TAG and less protein

hence, least dense.
Have ApoB-48, ApoE, and ApoC-II
ApoC-II activates lipoprotein lipase
to allow FFA release for fuel in
adipose tissue, heart, and skeletal
muscle
 Chylomicron remnants
deposit their cholesterol
in the liver
When chylomicrons are depleted of
their TAG, remnants go to liver
ApoE receptors in liver bind the
remnants, take them up by
endocytosis
Remnants release their cholesterol
in the liver
VLDLs transport endogenous
lipids
Cholesteryl esters and TAGs from
excess FA and cholesterol are
packed into very low-density
lipoproteins (VLDL)
Excess carbohydrate in the diet can
also be made into TAG in the liver
and packed into VLDL
Contain apoB-100, apoC-I, apoC-II,
apoC-III, and apoE
 VLDLs take TAGs to
adipose tissue and muscle
Again, ApoC-II activates lipoprotein
lipase to release free fatty acids
Adipocytes take up the FFA,
reconvert them to TAGs, and store
them in lipid droplets
Muscle uses the TAG for energy
 VLDL remnants become
LDL
Removal of TAG from VLDL
produces LDL
Because TAG removed, LDL is
enriched in cholesterol/chloesteryl
esters
ApoB-100 is the major
apolipoprotein
 Familial hypercholesterolemia
is associated with LDL receptor
mutations
Mutations in LDL receptor prevent
normal uptake of LDL by liver and
other tissues
LDL accumulates in blood
Homozygous individuals have
much increased risk of heart attack
Heterozygous individuals have risk
of heart attack greater than normal
 HDL carries out reverse
cholesterol transport
HDLs contain a lot of protein
Including ApoA-I and
lecithin-cholesterol acyl transferase (LCAT)
Catalyzes the formation of cholesteryl esters from lecithin
and cholesterol
Enzyme converts the cholesterol of chylomicron
and VLDL remnants to cholesteryl esters
HDL picks up cholesterol from cells and returns
them to the liver
See Fig. 21-42
 Regulation of HMG-CoA
Reductase by Proteolytic
Degradation
Insig (insulin-induced gene
protein) senses cholesterol levels.
Triggers ubiquination of HMG-CoA
reductase
Targets the enzyme for degradation
by proteasomes
The genes activated by LXR-
RXR are largely for
cholesterol transport
Acetyl-CoA Carboxylase
First enzyme in fatty acid synthesis
Apoproteins (C1, C2, D, and E)
For cholesterol transport
GLUT4
ABC transporters
For reverse cholesterol transport
 Review of Cholesterol
Regulation
Insulin cascades stimulate HMG-
CoA reductase
Transcription increases when
cholesterol levels are low
SREBPs activated
Transcription slows when
cholesterol levels are high
LXRs activated
 How Plaques Form

LDL with partly oxidized fatty acyl groups

sticks to the lining of arteries
Attracts macrophage cells of the immune
system
These cells dont regulate their uptake of
sterols, so they accumulate cholesterol
and cholesteryl esters
The macrophages become foam cells
(named for appearance)
How Plaques Form (cont.)

Foam cells undergo apoptosis

Remnants accumulate, along with
scar tissue, etc.
Can occlude a blood vessel or break
off and travel to another artery
Occlusion of blood vessels in the
heart cause heart attack; occlusion in
the brain causes stroke
 Familial
Hypercholesterolemia
Due to genetic mutation in LDL receptor
Impairs receptor-mediated uptake of
cholesterol from LDL
Cholesterol accumulates in the blood and in
foam cells
Regulation mechanisms based on
cholesterol sensing inside the cell dont
work
Homozygous individuals can experience
severe CVD as youths
Statin drugs inhibit HMG-
CoA reductase to lower
cholesterol
Statins resemble mevalonate competitive
inhibitors of HMG-CoA reductase
First statin, lovastatin, found in fungi
Lowers serum cholesterol by tens of percent
Side-effects include muscle weakness,
coenzyme Q depletion
Also reported to improve circulation, stabilize
plaques by removing cholesterol from them,
reduce vascular inflammation
Reverse cholesterol transport by
HDL explains why HDL is
cardioprotective
HDL picks up cholesterol from non-
liver tissues, including foam cells at
growing plaques
ABC (ATP-Binding Cassette)
transporters bring cholesterol from
inside the cell to the plasma
membrane
HDL carries cholesterol back to liver
 There are several classes of
cholesterol-derived steroids
Adrenal gland-synthesized steroids:
Mineralcorticoids
Control electrolyte balance, reabsorption of
Na+, Cl, HCO3 from kidney
Glucocorticoids
Regulate gluconeogenesis, reduce
inflammation
Gonad-synthesized steroids:
Progesterone, androgens, estrogems