Download Cholesterol Metabolism_MJH

Cholesterol
Dr. M. Jawad Hassan
Theme: Chest Pain
Objectives
1- Structure and Metabolism (absorption,
synthesis, and fate) of Cholesterol
2- Regulation of Cholesterol Synthesis
3- Synthesis and fate of bile salts and bile
acids
4- Bile salt deficiency (cholelithiasis)
Cholesterol sources, biosynthesis
and degradation
• diet
– only found in animal fat
• biosynthesis
– primarily synthesized in the liver from acetyl CoA
– 27 C cyclic compound
• degradation
– only occurs in the liver
– cholesterol is converted to bile acids
Lipids circulate in the blood in
several forms
• Cholesterol
– Free cholesterol
– Cholesterol ester
• Phospholipids
• Triglycerides
• Free fatty acids
6 Year CHD Death Rate
per 1,000 Men
Serum Cholesterol and CHD
in 361,662 U.S. Men
18
16
14
12
10
8
6
4
2
0
140
160
180
200
220
240
260
280
300
Serum Cholesterol
Martin M. Lancet 1986;11:933-936
Biosynthesis of cholesterol
- synthesis of acetoacetyl CoA
Biosynthesis of cholesterol
- synthesis of mevalonate
rate-limiting step
and step subject to
inhibition by statins
Biosynthesis of cholesterol
-synthesis of isopentenyl
-pyrophosphate
A
monoterpene
Biosynthesis of cholesterol
- synthesis of squalene
a sesquiterpene
a triterpene
Biosynthesis of cholesterol
- synthesis of lanosterol
Biosynthesis of cholesterol
ACAT inhibitors act
here
Biosynthesis summary
19 steps
HO
HO
lanosterol
cholesterol
Conversion of lanosterol to cholesterol involves
19 reactions, catalyzed by enzymes in ER
membranes.
Additional modifications yield the various steroid
hormones or vitamin D.
Many of the reactions involved in converting
lanosterol to cholesterol and other steroids are
catalyzed by members of the cytochrome P450
enzyme superfamily.
The human genome encodes 57 members of the
cyt P450 superfamily, with tissue-specific expression
and intracellular localization highly regulated.
 Some P450 enzymes are localized in
mitochondria.
 Others are associated with endoplasmic
reticulum membranes.
Regulation of Cholesterol Synthesis
1- Sterol-Dependent regulation of gene
expression
– SREBP-2 (Sterol regulatory element binding
protein 2)
– Low sterol-SREBP2-SCAP (SREBP2
cleavage-activating protein) association and
cleavage in ER
– Act as transcription factor for SRE
– Sterol abundance—binding to SCAP at sterol
sensing domain
The SREBP precursor
protein is embedded in
the endoplasmic
reticulum (ER)
membrane via two
transmembrane ahelices.
ER lumen
membrane
SCAP
binding
domain C
cytosol
N
SREBP
domain
The N-terminal SREBP domain, which extends into
the cytosol, has transcription factor capability.
The C-terminal domain, also on the cytosolic side of
the membrane, interacts with a cytosolic domain of
another ER membrane protein SCAP (SREBP
cleavage-activating protein).
SCAP has a
transmembrane sterolsensing domain
homologous to that of
HMG-CoA Reductase.
PreSREBP-SCAP/sterol-Insig
(in ER)
sterol
PreSREBP-SCAP-Insig
Insig
When bound to a sterol,
PreSREBP-SCAP
the sterol-sensing domain
(translocates to golgi)
of SCAP binds the ER
membrane protein Insig.
Association with Insig causes the SREBP-SCAP
precursor complex to be retained within the ER.
When sterol levels are low, SCAP & Insig do not
interact.
This allows the SCAP-SREBP precursor complex to
translocate from the ER to the golgi apparatus.
 Protease S1P (site
one protease), an
integral protein of golgi
membranes, cleaves
the SREBP precursor
at a site in the lumenal
domain.
golgi
lumen
SCAP-activated
S1P cleavage
membrane
C
N
S2P cleavage
releasing
SREBP
cytosol
 An intramembrane zinc metalloprotease domain
of another golgi protease S2P then catalyzes
cleavage within the transmembrane segment of the
SREBP precursor, releasing SREBP to the
cytosol.
Only the product of S1P cleavage can serve as a
substrate for S2P.
PDB 1AM9
The released SREBP
enters the cell nucleus
where it functions as a
transcription factor to
activate genes for
enzymes of the
cholesterol synthesis
pathway.
Its lifetime in the nucleus
is brief, because SREBP
is ubiquitinated &
degraded.
Diagram (in article by P. J. Espenshade;
requires J. Cell Sci. subscription)
SREBP-DNA
complex
Homodimeric DNA-binding domain of
SREBP interacting with a sterol
regulatory element DNA segment.
2- Sterol-accelerated enzyme degradation
• sterol itself act as sterol sensing integral
protein
• High sterol levels accelerate binding of
insig and proteosomal degradation of
HMG CoA Reductase
3- Sterol independent phosphorylation /
dephosphorylation
• Adenosine monophosphate –activated protein
kinase (AMPK) and phosphoprotein
phosphatase
• Phosphorylated form is inactive
• AMPK activated by AMP
• Cholesterol synthesis decreased with decrease
in ATP availability
4- Hormonal Regulation
• Increase in insulin or thyroid hormones
favors up-regulation of expression of HMG
co A reductase gene
• Cortisol and glucagon have decreasing
effect
Pathways Affecting Cholesterol
Balance
Liver
(Intake)
(Excretion)
ABCA1
HMG CoA Reductase
(Esterification)
(Synthesis)
(Bile
Acids)
(Micellar
Cholesterol)
(Uptake)
5- ANTI-CHOLESTEROL DRUGS
They are reversible competitive inhibitors of
HMG CoA Reductase: (The Statins)
Simvastatin(Zocor)
Lovastatin(Mevacor)
Atorovostatin(Lipitor)
Fluvastatin(Lescol)
Degradation of cholesterol
Bile acids and salts
• formed from cholesterol in the liver
• stored in the gall bladder in bile as bile salts
• utilized during digestion of fats and other lipid
substances (act as detergents, emulsification)
• rate limiting step is the conversion of cholesterol
to 7-alpha cholesterol by 7-a-hydroxylase
Bile acids
• cholic acid is the bile acid found in the
largest amount in bile
• cholic acid and chenodeoxycholic acid are
referred to as primary bile acids
• bile acids are converted to either glycine
or taurine conjugates (in humans the ratio
of glycine to taurine conjugates is 3:1)
Approximate composition of bile salts
•
•
•
•
•
•
•
Glycocholate – 24%
Glycochenodeoxycholate – 24%
Taurocholate – 12%
Taurochenodeoxycholate – 12%
Glycodeoxycholate- 16%
Taurodeoxycholate – 8%
Various lithocholate – 4%
Bile acids
• fat digestion products are absorbed in the first
100 cm of small intestine
• the primary and secondary bile acids are
reabsorbed almost exclusively in the ileum
returning to the liver by way of the portal
circulation (98 to 99%)
• this is known as the entero-hepatic circulation
• less than 500 mg a day escapes re-absorption
and is excreted in the feces
Bile salts
• detergent character of bile salts is due to
the hydrophobic-hydrophilic nature of the
molecules
• the presence of hydroxyl (or sulfate) and
the terminal carboxyl group on the tail
gives the molecule its hydrophilic face
• the steroid ring with its puckered plane
provides the hydrophobic face
Function of bile salts
• emulsification of fats due to detergent activity
• aid in the absorption of fat-soluble vitamins
(especially vitamin K)
• accelerate the action of pancreatic lipase
• have choleretic action –stimulate the liver to
secrete bile
• stimulate intestinal motility
• keep cholesterol in solution (as micelles)
Mixed micelle formed by bile salts, triacylglycerols
And pancreatic lipase
BILE ACIDS
CH3
HO
CH3
CH3
CH3
12
H
CH3
H
3
7
COOH
COOH
H
CH3
H
H
H
HO
OH
H
H
CHOLIC ACID
CHOLANIC ACID
CH3
CH3
CH3
COOH
CH3
COOH
H
CH3
H
CH3
H
H
H
H
OH
HO
H
HO
OH
H
CHENODEOXYCHOLIC ACID (CHENODIOL)
(CHENIX)
URSODEOXYCHOLIC ACID (URSODIOL)
(ACTIGALL)
Entero-Hepatic Circulation
• Entero-hepatic circulation of bile salts (excretion
into intestines and re-absorption in to liver)
• Bile acid squestrants (cholestyramine), binds
bile acids in gut, prevent their re-absorption and
promote excretion.
• Treatment of Hypercholesterolemia (removal of
bile acids promote synthesis of bile acids in liver,
so more cholesterol removal).
• Dietary fiber has same effect.
Cholelithioasis
• Gross malabsorption of bile acids from
intestine
• Obstruction of Biliary tract
• Sever hepatic dysfunction
• Increase biliary cholesterol excretion with
the use of fibrates (up regulation of fatty
acid beta oxidation)