 Contents :

 Introduction
 Cholesterol synthesis
 Regulation of cholesterol synthesis

By : Savath Sovannak
 Cholesterol, the characteristic steroid alcohol of animal tissues, performs a number of
essential functions in the body.
 Incorporated in al cell membranes
 Precursor for synthesis of
o Steroid hormone
o Bile acids
o Vitamin D
 Source of cholesterol :
 Endogenous: Cholesterol is formed in the body almost in all nucleated cells from Acetyl-
CoA, although liver, intestine, adrenal cortex, and reproductive tissues, including
ovaries, testes, and placenta, make the largest
 Exogenous: Cholesterol occurs only in food of animal origin such as egg yolk, meat,
liver....
 Excretion :
 Humans cannot metabolize cholesterol to carbon dioxide and water because of absence
of enzymes capable of catabolizing the steroid ring  it is excrete in the bile either as
cholesterol or after conversion to bile acids (Salt)
 Moreover, some dietary cholesterol is excreted in feces without being absorbed
 Some of cholesterol in intestine is act on by intestinal bacterial enzymes and converted
to neutral sterols (coprostanol, cholestanol) before excretion
By : Savath Sovannak
 Location :
 Intracellular location : Cytosol
 Organ location :
o Liver is the major site of cholesterol synthesis.
o Other tissues : intestine, adrenal cortex, gonads, skin……
 Precursor: Acetyl-CoA.
 Step :
 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthesis
o First, two acetyl CoA molecules condense to form
acetoacetyl CoA by thiolase
o Next, a third molecule of acetyl CoA is added by HMG
CoA synthase, producing HMG CoA, a six-carbon
compound
 Mevalonate synthesis
o HMG CoA is irreversible reduced to mevalonate by HMG
CoA reductase
• HMG CoA reductase is an integral membrane protein
of the SER
o It occurs in the cytosol, uses two molecules of NADPH as
the reducing agent, and releases CoA
By : Savath Sovannak
  Cholesterol synthesis from mevalonate
1. Mevalonate is converted to 5-
pyrophosphomevalonate in two
steps, each of which transfers a
phosphate group from ATP.
2. 5-pyrophosphomevalonate is
decarboxylated to isopentenyl
pyrophosphate (IPP). The reaction
requires ATP
3. IPP is isomerized to 3,3-
dimethylallyl pyrophosphate
(OPP).
4. IPP and OPP condense to form 10-
carbon geranyl pyrophosphate
(GPP).
5. Second molecule of IPP condenses
with GPP to form 15-carbon
farnesyl pyrophosphate (FPP).
6. Two molecules of FPP combine,
releasing pyrophosphate, and are
reduced, forming the 30 carbon
compound squalene.
7. Squalene undergoes two reactions catalyzed by SER-associated enzymes that use molecular oxygen (02)
and NADPH  its linear structure is folded and cyclized to form lanosterol
8. The conversion of lanosterol to cholesterol is a multistep process involving :
o shortening of the carbon chain from 30 – 27 by oxidative removal of three methyl groups
o reduction of one double bond between C24-C25
o Migration of the double bond from C8 to C5
By : Savath Sovannak
  Feedback regulation :
 Cholesterol end product of pathway as well as mevalonate and
cholesterol from diet  (-) synthesis of HMG-CoA reductase
o Cholesterol also acts as feedback inhibitor of HMG CoA
reductase
 Bile salt or bile acid also (-) synthesis of HMG-CoA reductase
 Sterol regulatory element-binding proteins (SREBPs)
 When cholesterol intracellular is high  SREBP-2 bind to SER
membrane protein, SREBP cleavage-activating protein (SCAP) and
binding of SCAP to other ER membrane proteins, insulin-induced
gene proteins (INSIG)  preventing activation of SREBP-2  ↓ HMG
CoA reductase synthesis and ↓ LDL receptors synthesis
 When cholesterol intracellular is Low 
SREBP-2-SCAP complex moves from ER to
Golgi  generate a soluble fragment that
enters nucleus and binds sterol regulatory
element (SRE)  ↑ HMG CoA reductase
synthesis and ↑ LDL receptors synthesis
 Sterol-independent phosphorylation
/dephosphorylation
 Adenosine monophosphate-activated protein
kinase (AMPK)  (-) HMG-CoA reductase by
phosphorylation
o Epinephrine and glucagon  ↑PKA  phosphorylate and activate AMPK
 Phosphoprotein phosphatase  (+) HMG-CoA reductase by dephosphorylation
o Insulin  (+) protein phosphatase  dephosphorylate and activate HMG-CoA reductase
By : Savath Sovannak
 Drug Inhibition:
 Statins (HMG-CoA Reductase Inhibitors) : atorvastatin, fluvastatin, lovastatin,
pitavastatin, pravastatin, rosuvastatin, and simvastatin
 The statins are structurally related to hydroxymethylglutaryl (HMG)-CoA, which is the
substrate for HMG-CoA reductase  competitive inhibitors of HMG CoA reductase 
inhibiting de novo cholesterol synthesis  deplete the intracellular supply of cholesterol
 causes the cell to increase the number of cell surface LDL receptors that can bind and
internalize circulating LDL-C  plasma cholesterol is reduced, by both decreased
cholesterol synthesis and increased LDL-C catabolism
By : Savath Sovannak