Cholesterol Metabolism

Dr Abeerah Zainub
Assistant Professor
Biochemistry
 Learning Objectives

• Describe Synthesis Of Cholesterol And Its Regulation

• Relate The Role Of Statins With The Treatment Of
Hypercholesterolemia
• Describe The Degradation Of Cholesterol
 Cholesterol

The characteristic steroid alcohol of

animal tissues.

Essential • structural component of all cell

membranes, modulating their fluidity
functions in • precursor of bile acids, steroid hormones,
the body and vitamin D.
Cholesterol
It is the major sterol (Steroid
Alcohol) found in the animals.

A hydrophobic compound containing a

“steroid nucleus” at the center
consisting of 4 fused rings (A-D) attached
with an 8 carbon chain to carbon 17 of D.

Other notable features;

• -OH group at Carbon 3 of ring A.
• Double bond between carbon 5 & 6 of ring B.
 Cholesteryl esters

• It is an Esterified form of cholesterol that is even more

hydrophobic than cholesterol.
• They are cholesterols having a fatty acid attached at carbon 3.
• Cholesteryl esters are not found in membranes and are
normally present only in low levels in most cells.
• Because of their chemical nature they need to be transported
in association with proteins (Lipoproteins) or be solubilized
by bile salts.
Cholesterol Homeostasis

Liver plays a central role in

Body’s cholesterol
homeostasis by managing;
• The influx in the forms of
• dietary cholesterol
• de novo cholesterol
• The efflux in the forms of
• Bile salts
• Plasma lipoproteins
 Mediation of Dietary Cholesterol

• Intestinal uptake of cholesterol is in part mediated by niemannpick

c1-like 1 protein (NPC1-L1) (A drug ezetimibe that reduces
absorption of dietary cholesterol, targets (NPC1-L1).
• Plant sterols (phytosterols), such as βsitosterol, are poorly
absorbed by humans (5% absorbed as compared to 40% for
cholesterol).
• After entering the enterocytes, they are actively transported
back into the intestinal lumen along with some cholesterol.
• Thus they reduce Cholesterol absorption and are used as a dietary
 Synthesis Of Cholesterol
• virtually all human tissues,
In • Mostly in liver, intestine, adrenal cortex, and reproductive
Or
ga tissues, including ovaries, testes, and placenta.
ns:

Wit • in both the cytosol and the membrane of the smooth

hin endoplasmic reticulum (ER).
the
Cel
l:
• Acetyl coenzyme A (CoA), nicotinamide adenine
Ess dinucleotide phosphate (NADPH) and adenosine triphosphate
ent
ials (ATP).
:
 Synthesis of 3-Hydroxy-3-
MethylGlutaryl Coenzyme A
First, two Acetyl CoA molecules
condense to form Acetoacetyl CoA.
Next, a third molecule of Acetyl CoA is
added by HMG CoA synthase,
producing HMG CoA, a six-carbon
compound.
In Liver parenchymal cells HMG-Co-A
synthase is present in
• Cytosol (used in cholesterol synthesis)
• Mitochondria (used in Ketone Body synthesis)
 Rate Limiting, Key Regulated,
Committed Step: Synthesis of
mevalonate
• In this step Reduction of HMG
CoA to Mevalonic Acid by using
2NADPH molecules.
• The enzyme required for this is
HMG CoA reductase which is an
integral membrane protein of
the ER, with its catalytic
domain projecting into the
cytosol.
 Synthesis Of Cholesterol

• [1] A 2 step of phosphorylation using ATPs convert

Mevalonate is to 5-PyroPhosphoMevalonate.
• [2] Then 5-PyroPhosphoMevalonate is decarboxylated
to a five-carbon isoprene unit, Isopentenyl
PyroPhosphate (IPP). The reaction requires ATP.
• IPP is the precursor of the isoprenoids including
• Cholesterol (a sterol isoprenoid).
• Dolichol and ubiquinone, or coenzyme Q (Non-sterol isoprenoids).
 Synthesis Of Cholesterol

• [3] IPP is isomerized to 3,3-Dimethylallyl

PyroPhosphate (DPP).
• [4] IPP and DPP condense to form ten-carbon Geranyl
PyroPhosphate (GPP).
• [5] Another molecule of IPP then condenses with GPP
to form 15-carbon Farnesyl PyroPhosphate (FPP).
• Note: FPP provides footing for the anchoring proteins (e.g
Ras) through Prenylation i.e covalent attachment.
 Synthesis Of Cholesterol

• [6] two molecules of FPP combine, releasing

pyrophosphate, and are reduced, forming the 30-carbon
compound squalene.
• Note: A total of 6 isoprene units (IPP) are used to form squalene. As
for one IPP 3 ATPs are utilized, a total of 18 ATPs are required to
make polyisoprenoid squalene.
• [7] squalene is converted to lanosterol (sterol) by a
sequence of reactions catalyzed by ER-associated enzymes
 Synthesis Of Cholesterol

• [8] the conversion of lanosterol to cholesterol is a

multistep, ER-associated process involving
• shortening of the side-chain,
• oxidative removal of methyl groups,
• reduction of double bonds, and
• migration of a double bond.
 Synthesis Of Cholesterol

• Smith-lemli-opitz syndrome (SLOS), an autosomal-recessive

disorder of cholesterol biosynthesis, leading to multisystem
embryonic malformations.
• It is caused by a partial deficiency in 7-dehydrocholesterol-
7-reductase, the enzyme that reduces the double bond in 7-
dehydrocholesterol (7-DHC), thereby converting it to cholesterol.

• Note: 7-DHC is converted to vitamin D3 in the skin.

 Regulation Of Cholesterol
Synthesis
Sterol-dependent Regulation Of Gene Expression

Sterol-accelerated Enzyme Degradation

Sterol-independent Phosphorylation/Dephosphorylation

Hormonal Regulation

Inhibition By Drugs
 Sterol-dependent Regulation Of
Gene Expression
• Sterol Regulatory Element Binding Protein (SREBP):
Transcription factor for HMG Co-A Reductase
• SREBP Cleavage Activating Protein (SCAP).
• SREBP is an Integral Protein of the Endoplasmic Reticulum
where it is attached to SCAP.
• An SREBP-SCAP complex is present in ER.
Sterol-dependent Regulation Of
Gene Expression
 Sterol-dependent Regulation Of Gene
Expression

• When sterol levels are low SREBP-SCAP complex moves to

Golgi where Proteases cleave it.
• Free SREBP enters the nucleus and attaches with Sterol
Regulatory Element (SRE), acting as a transcription factor for
HMG-CoA Reductase enzyme.
• When sterols are abundant, SREBP attaches with SCAP and
other proteins of ER like insulin induced gene (insig) product.
• This keeps the SREBP in ER and it does not form SREBP-2
transcription factor, thus downregulates Cholesterol synthesis.
 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.
• Binding leads to ubiquitination and proteasomal degradation
of the reductase.
 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: because AMPK is activated by AMP, cholesterol synthesis, like fatty
acid synthesis, is decreased when ATP availability is decreased.
 Hormonal Regulation

• The amount of HMG CoA reductase (quantity) is controlled

hormonally.
• 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,

pravastatin, rosuvastatin, and simvastatin)
are structural analogs of HMG CoA, and
are metabolized to reversible, competitive inhibitors of HMG CoA
reductase.

They are used to decrease plasma cholesterol levels in patients

with hypercholesterolemia.
 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,

a small percentage of which is excreted in the feces,

and by secretion of cholesterol into the bile, which
transports it to the intestine for elimination.
 Degradation of Cholesterol

By the action of intestinal bacteria the cholesterol

is reduced to
• Coprostanol
• Cholestanol
Together with cholesterol, these compounds make
up the bulk of neutral fecal sterols.
Impact of Various Factors on Metabolic
Homeostatic State of the body
Disturbance in Homeostasis Leads to

gradual deposition of cholesterol in the tissues,

particularly in the endothelial linings of blood vessels

leads to plaque formation, causing the narrowing of

blood vessels (atherosclerosis)

increased risk of cardio-, cerebro-, and peripheral

vascular disease
“ Respect
Nature always pays off it’s debts.
it and it will respect you back.
Protect it and it will protect you back.
Facilitate it and it will facilitate you
back.
”
Thank you..!