Cholesterol and Lipoprotein Metabolism

8/8/2019 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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Documents

Cholesterol and Lipoprotein Metabolism