Cholesterol and Lipoprotein Metabolism
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Transcript of Cholesterol and Lipoprotein Metabolism
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Cholesterol and Lipoprotein
Metabolism
Ricardo R. Santos, MD
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Structure of Cholesterol
An alicyclic compound whose structureinclude:
Cyclopentanoperhydrophenanthrene nucleus
Single hydroxyl group at C-3 Double bond between C-5 and C-6
Eight-membered branched hydrocarbon chainattached to ring D at C-17
Two angular methyl groups: a) one designated C-18 attached to C-13; b) second designated C-19attached to C-10
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Two forms of cholesterol
1. Free cholesterol- unesterified to fatty acid; amphipathic- found in membranes and outer layer
of lipoproteins
- 30% of total cholesterol in the blood
- biologically active form
2. Cholesterol ester
- fatty acid is esterifed to OH grp at C-3- found in lipid core of lipoproteins
- 70% of total cholesterol in the blood
- storage form of cholesterol in the tissue
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Cholesterol Values
Plasma: 150 200 mg/100 ml
(mostly as cholesterol ester)
Bile: 390 mg/100 ml
(mostly as free cholesterol; 96% of
total)
Total cholesterol is estimated byLiebermann-Burchard reaction
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Importance of Cholesterol
Important component of membranes andouter layer of lipoproteins
Precursor of:
- vitamin D3 (skin)
- bile acids (liver)
- steroid hormones (adrenals and gonads)
Protects gallbladder membrane fromirritating and harmful effects of bile salts
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Foods rich in cholesterol
Cholesterol is primarily of animal origin
- skin, liver, intestines, adrenal gland,gonads, brain
Egg yolk, meat
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Medical importance of cholesterol
Atherosclerosis
Gallstones
Hyperlipoproteinemias
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Biosynthesis of Cholesterol
General considerations- Liver, intestine, adrenal cortex, gonads, placenta
have the greatest capacity to synthesize chol.
- All carbon atoms of cholesterol are derived from
acetyl CoA.
- Cholesterol synthesis takes place in the cytosoland endoplasmic reticulum; 700 mg/day
- Synthesis is expensive (18 ATPs/cholesterol)
- Reducing power in the form of NADPH isprovided by HMP shunt
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Five Steps in the Synthesis of Cholesterol
1. Biosynthesis of mevalonate
2. Formation of isoprenoid units
3. Formation of squalene
4. Cyclization of squalene to lanosterol
5. Conversion of lanosterol to cholesterol
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Step 1 Formation ofMevalonate(Rate-limiting Step)
Acetyl CoAThiolase
CoA
Acetoacetyl CoA
HMG-CoA synthase Acetyl CoA
(cytosolic)
CoA
3-Hydroxy-3-methylglutaryl CoA
(HMG-CoA)
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From HMG-CoA to Mevalonic Acid
HMG-CoA
HMG-CoA reductase NADPH
(committed enzyme)
NADP
Mevalonate
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Regulation of HMG-CoA Reductase
HMG-CoA reductase is an intrinsic membrane protein
of the endoplasmic reticulum and its active siteextends into the cytosol.
1. Feedback inhibition by cholesterol
2. Hormonal regulation* Insulin stimulates (favor dephosphorylated
active form of enzyme)
* Glucagon inhibits (favor phosphorylated
inactive form of enzyme)
3. Cholesterol-mediated inhibition of genetranscription
4. Inhibition by drugs: statins e.g., simvastatin,
lovastatin, pravastatin, atorvastatin, etc.
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Regulation of Cholesterol Synthesis
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Step 2. Formation of isopentenylpyrophosphate
Sequential phosphorylation of mevalonateby kinases utilizing ATP
Take place several times
Need six isoprenoid units to form onecholesterol
Most expensive stage
1 mevalonate to 1 isoprenoid unit = 3 ATPs
6 isoprenoid units to 1 cholesterol = 18 ATPs
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Step 3. Formation of Squalene
Involves initial isomerization of isopentenylpyrophosphate.
Followed by a series of condensation reactionsforming geranyl pyrophosphate and
farnesylpyrophosphate.
Condensation of two farnesylpyrophosphatesforming the 30-carbon atom squalene.
P
yrophosphate is released in eachcondensation step.
Isopentenyl-PP is a precursor of importantcompounds like ubiquinone and dolichol.
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Synthesis of CholesterolSynthesis of Cholesterol
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Step 4. Formation of Lanosterol
Involves cyclization of squalene to formlanosterol by endoplasmic reticulum-boundsqualene oxidocyclase
Squalene oxidocyclase has two enzymaticactivities: epoxidase (monooxygenase) andcyclase (oxidosqualene:lanosterol cyclase)
Lanosterol has also 30 carbon atoms
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Synthesis of CholesterolSynthesis of Cholesterol
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Step 5. From Lanosterol to Cholesterol
Takes place in the membrane of endoplasmicreticulum
The major pathway in mammals proceeds
through 7-dehydrocholesterol involving aseries of double bond reductions anddemethylations.
Alternative pathway involves:1. three demethylations to give zymosterol
2. isomerization of double bond to form desmosterol
3. reduction of double bond to form cholesterol
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Major and alternative routes from lanosterolto cholesterol
Lanosterol
Major route Alternative route
7-dehydrocholesterol Zymosterol
Desmosterol
Cholesterol
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Metabolism of Cholesterol
Metabolism of Cholesterol
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Mutations on LDL ReceptorMutations on LDL Receptor
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Fate of Endogenous Cholesterol
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Plaque Formation in Atherosclerosis
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Oxidized LDL and plaq
ue formation
Oxidized LDL and plaq
ue formation
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Fatty Streak of AtherosclerosisFatty Streak of Atherosclerosis
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Fibrofatty plaq
ue of Atherosclerosis
Fibrofatty plaq
ue of Atherosclerosis
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Intraluminal Thrombus
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