* Biosynthesis of Cholesterol, Steroids and Isoprenoids
- Important lipid
1- structural lipid present in membrane.
2- precursors of steroidal hormones.
- 27 C of cholesterol is
derived from acetate.
* The isoprene units are key intermediates in pathway from acetate to
cholesterol and also they are precursors to many natural lipids
Cholesterol is NOT important to be in the diet because it can be synthesized in all of the cells.
Cholesterol is made of
Acetyl CoA in four
stages
6 Carbon
5 Carbon
30 Carbon
27 Carbon
Cystolic - hydroxy - methyl
glutaryl CoA synthase
In the cytosol
(HMG CoA synthase)
Is different from HMG-CoA
synthase in the mitochondria
in keton body formation.
The committed step HMG-CoA
reductase : integral protein in
endoplasmic reticulum and it is a
point of regulation.
Biosynthesis of Cholesterol
Biosynthesis of Cholesterol
* Cholesterol has several fates :
- Most of cholesterol is synthesized in liver, a little amount is
synthesized in the cells.
- Small fraction is incorporated into the cell membrane of hepatocytes.
- Most of it is exported in one of three forms.
- Bile acids and salts.
- Cholesterol esters formed in the liver by acyl- CoA- cholesterol acyl
transferase (ACAT)
- Adrenal gland and gonads use cholesterol for sex hormonal
biosynthesis and vitamin D.
* Degradation of cholesterol
- The ring structure of cholesterol cannot be oxidized or metabolized
into CO2 and H2O in humans, So intact ring is eliminated in form of :
1- Bile salt that eliminated by feces.
2- Secretion of cholesterol into bile, that also go with feces.
- Some cholesterol is modified by normal flora to give Cholestanol and
Caprostanol
* Regulation of cholesterol synthesis
1- Feed back inhibition.
- Cholesterol is a feed back inhibitor of HMG-CoA reductase
decrease cholesterol synthesis.
- HMG-CoA reductase activity is the rate limiting step in the biosynthesis of
cholesterol and subjected to different controls.
2- Hormonal regulation of cholesterol biosynthesis.
- HMG- reductase is controlled by Glucagon and Insulin.
- Glucagon
increase formation of inactive (phosphorylated) form of
the enzyme
decrease cholesterol biosynthesis.
- Insulin
increase formation of active (unphosphorylated) form of the
enzyme
increase cholesterol biosynthesis.
3- Sterol-mediated regulation of transcription.
- cholesterol taken by cells from lipoproteins
decrease biosynthesis
of cholesterol by decrease of transcription of DNA of the HMG-CoA
reductase enzyme.
4- Inhibition of drugs.
Lovastatin and Mevastatin are competitive inhibitors of HMG-CoA reductase.
* Regulation of cholesterol synthesis
* Regulation of cholesterol synthesis
* Bile acids and Bile salts
- Bile consist of a watery mixture of organic
and inorganic compounds. Bile can go from the
liver directly to the intestine or to be stored at
bilary gland.
- The most common bile acid : Cholic and
Chenodeoxycholic acid.
- Bile acids are not fully ionized at pH = 7
because they have pKa = 6, (they are
amphipathic compounds)
Synthesis of bile acids
- Synthesized in the liver.
- Reduction of the double
bond, insertion of hydroxyl
groups and shortening of
cholesterol.
- The rate limiting step is
insertion of -OH group at
C7, by 7 -hydroxylase.
Action of intestinal flora
1- removing of glycin and
taurine
2- modification at the bile
acids to produce secondary
bile acids (removing OH
groups)
deoxycholic acid and
lithocholic acid.
Synthesis of bile salts
- Bile acids are released from liver. They conjugated with amino acid Glycin or
Taurine by amide linkage and called bile salts
- glycocholic and glycochenodeoxycholic acid
- taurocholic and taurochenodeoxycholic acid
- The addition of glycin or taurine
decrease pKa
increase ionization
of these compounds at pH = 7.4 because of the presence of COO- and sulfate
- Bile salts are more effective detergent than that of bile acids
- only bile salts, are found in the bile,
Bile acids and Bile salts
Biosynthesis of steroidal
hormones
steroidal hormones are derived
from cholesterol
Adrenal cortex
mineralocorticoids
glucocorticoids
Sex hormones are
synthesized in male and
female Gonads
* Cholesterol and other lipids are carried on plasma lipoproteins:
- cholesterol, cholesterol esters and other lipids are essentially insoluble in water.
To be moved from one part to another they should carried as plasma lipoprotein.
Plasma lipoproteins
- Macromolecular complexes of lipids and specific proteins called apolipoprotein
with a various combination of phospholipids, cholesterol, cholesterol esters and TG.
* Function : to keep the lipid soluble for transporting them between organs and
also provide efficient mechanism for delivering their lipid contents to the tissues.
* Composition of plasma lipoproteins
- TG and cholesterol esters are mainly carried by lipoprotein (In the core : TG +
cholesterol ester, In the surface : hydrophilic parts of cholesterol, phospholipids
and hydrophilic parts of apolipoproteins.
Apolipoproteins : the free form, have several functions , structural component,
recognition sites, activators or coenzymes.
* Size and density of lipoprotein particles
different combinations of lipids and proteins produce different particles that
differ in densities ranging from lowest density Chylomicrons to HDL (high density
lipoprotein) can be separated by ultra centrifugation.
lipoproteins
Each class of lipoprotein has specific function determined by point of
synthesis, lipid composition and apolipoprotein content.
Apolipoproteins
classified A to H.
each class has
subclasses
* Metabolism of Chylomicrons
- The largest in size and least density of lipoproteins.
- Synthesized in the endoplasmic reticulum of epithelial cells that line the small
intestine, then they are packaged in secretory vesicles by Golgi and exported to
lymphatic system then enter the blood stream.
* The “nascent chylomicron” that released by intestinal mucosal cells contain
apo B-48 (unique for chylomicrons) then this nascent chylomicron is rapidly
modified receiving apo E and apo C.II from circulating HDL.
* Degradation of chylomicrons
lipoprotein lipase : (activated by apo C.II) hydrolyses TG in these particles into
free fatty acids and glycerol.
*Chylomicrons lipoprotein lipase chylomicron remnants (decrease size, increase
density)
- apolipoprotein C is returned to HDL and the remnant is taken up by hepatocytes.
- Receptors of hepatocytes recognize the remnant through apo E and apo B-48
activation of up taking by endocytosis
release cholesterol.
- The release of cholesterol regulate the cholesterol synthesis in the liver by
decrease HMG CoA reductase and also inhibit allosterically this enzyme.
* Metabolism of very low density lipoprotein (VLDL)
- Excess of F.A can be converted into TG in the liver and packaged with
specific apolipoprotein to form VLDL.
- F.A , excess CHO
1- can be converted into TG stored in adipocyte.
2- TG packaged into VLDL (liver)
* VLDL : TG, cholesterol, cholesterol esters, apo C.I, C.II, C.III, apo E.
* VLDL are transported in the blood from the liver to muscle and adipose
tissue.
VLDL lipoprotein lipase free F.A
- oxidation (myocytes) OR resynthesis of
TG (adipocytes)
* VLDL : produced in liver and composed mainly of TG and their function to
carry lipids from liver to peripheral tissues and are degraded by lipoprotein
lipase.
* Fatty liver : imbalance between hepatic TG synthesis and secretion of VLDL,
diseases as hepatitis, uncontrolled diabetes, chronic ethanol ingestion can
cause fatty liver.
* VLDL is released from the liver as nascent VLDL containing apo- 100 and apo
A.I and then it will take apo C.II and apo E from circulating HDL.
Metabolism of lipoproteins
* Modification of circulating VLDL : TG are removed from VLDL (decrease size ,
increase density)
- IDL : VLDL remnants
- apo C.II and apo E are returned to HDL
- cholesterol esters transfer from HDL to IDL by enzyme lecithin- cholesterol acyl
transferase
- The VLDL is converted into LDL in the plasma.
* Metabolism of LDL
- LDL particles have apo B-100, contain less TG, high concentration of
cholesterol and cholesterol esters.
- The primary function of LDL is to provide the peripheral tissue by cholesterol
and this process is Receptor- mediated endocytosis.
* apo B-100 is recognized by LDL- receptor
activate the degradation by
endocytosis.
- VLDL contains apo B-100, but can’t bind to LDL receptors. (the conversion of
VLDL into LDL)
exposes of the receptor- binding domain of apo B-100
* Fate of cholesterol
- cholesterol that enter the cell can be incorporated into the cell membrane or
can be reesterified by ACAT for storage as form of cholesterol esters.
* LDL also con be up taken by liver cells mediated by apo E.
cholesterol esters transfer
from HDL to IDL by enzyme
lecithin- cholesterol acyl
transferase
*Receptor- mediated endocytosis
Cholesterol is delivered from LDL into
the peripheral cells.
* LDL receptors
deficiency
elevation of plasma
LDL
increase
plasma cholesterol.
Type II hyperlipidemia
Peripheral
cell needs
cholesterol.
Receptor-Mediated endocytosis
* Effect of endocytosed cholesterol on cell cholesterol content.
Chylomicron remnant, HDL, LDL, drive cholesterol into liver cells decrease
cholesterol synthesis and content in three ways
* Metabolism of HDL
- Synthesized in the liver and small intestine as small, protein- rich particles that
contain little cholesterol and no cholesterol esters. (nascent HDL, depleted HDL)
- Contain apo A.I, C.II, C.III and others and
LCAT (lecithin- cholesterol acyl transferase)
PCAT (phosphatidyl choline- cholesterol acyl transferase)
- LCAT at the surface of nascent HDL converts the cholesterol and PL of
chylomicron as VLDL remnant to cholesterol esters that forms the core of HDL
and formation of mature spherical HDL particle.
- Then the cholesterol rich HDL returns to the liver where the cholesterol is
unloaded that can be converted into bile salts.
* Depleted HDL can be pick up cholesterol stored in extra hepatic tissues and
carry it to the liver in “ Reverse Cholesterol Transport ” pathway.
Nascent HDL binding cholesterol rich cell
from cell to the HDL
goes to the liver.
passive movement of cholesterol
- up taking of cholesterol from cells by enzyme LCAT and storing of cholesterol
ester in the core of HDL.
1-HDL as reservoir of apolipoproteins
It act as circulating reservoir of apo C.II that can be transferred to VLDL
and chylomicron.
And also takes back the apoprotiens before VLDL remnants and
chylomicron remnants are taken by the liver.
2-Up taking of free cholesterol
3-Esterification of free cholesterol into CE by LCAT.
* CE (cholesterol esters) that stored in HDL can be transferred into VLDL
and exchanged by TG or PE by CE transfer protein.
VLDL
LDL
CE is utilized by cells.
* Fate of HDL
- HDL is taken by liver by receptor- mediated endocytosis. And CE are
degraded and cholesterol can be repackaged in lipoprotein, converted into bile
acids or secreted into bile.
* Role of lipoproteins in heart disease
- high levels of cholesterol
increase risk of atherosclerosis
linked to high level of LDL, decrease HDL.
The End
* Bile acids and Bile salts
- Bile consist of a watery mixture of organic and inorganic compounds.
Bile can go from the liver directly to the intestine or to be stored at
bilary gland.
- The most common bile acid : Cholic and Chenodeoxycholic acid.
- Bile acids are not fully ionized at pH = 7 because they have pKa = 6,
(they are amphipathic compounds)
* Synthesis of bile acids
- Synthesized in the liver.
- Reduction of the double bond, insertion of hydroxyl groups and
shortening of cholesterol.
- The rate limiting step is insertion of -OH group at C7, by 7 hydroxylase.
* Synthesis of bile salts
- Bile acids are released from liver. They conjugated with amino acid
Glycin or Taurine by amide linkage and called bile salts
- glycocholic and glycochenodeoxycholic acid
- taurocholic and taurochenodeoxycholic acid
- The addition of glycin or taurine
decrease pKa
increase
ionization of these compounds at pH = 7.4 because of the presence
of COO- and sulfate
- Bile salts are more effective detergent than that of bile acids
- only bile salts, are found in the bile,
* Action of intestinal flora
1- removing of glycin and taurine
2- modification at the bile acids
to produce secondary bile acids (removing OH groups)
deoxycholic acid and lithocholic acid.