Metabolism of cholesterol and lipoproteinsvyuka-data.lf3.cuni.cz/CVSE1M0001/metabolism of...

Metabolism of cholesterol and

lipoproteins

EC

Josef Fontana

Overview of the lecture

• The importance of cholesterol for the

human body

• Formation and degradation of

cholesterol

• Transport of lipids in plasma -

metabolism of lipoproteins

The importance of cholesterol for

the human body

Cholesterol

• Component of cell membranes -

represents about 1/4 of all lipids in the

membrane

• Amphipathic character

• Stabilization of membrane and

reduction of its fluidity

• Important derivatives - bile acids,

steroid hormones and vitamin D

Steroid hormones

• Gestagens - progesterone

• Androgens - testosterone

• Estrogens - estradiol

• Glucocorticoids - cortisol

• Mineralocorticoids - aldosterone

Vitamin D

• Active hormone: calcitriol

• In the skin, 7-dehydrocholesterol is

photolyzed by ultraviolet light -

product is previtamin D3

• Ca2+ and phosphate levels

Vitaminy D

Formation and degradation of

cholesterol

Cholesterol synthesis - 3 phases

• 1) Synthesis of isopentenyl

diphosphate - active isoprene from

AcCoA

• 2) Condensation of 6 units of

isopentenyl diphosphate - squalene

• 3) Cyclization of squalene to

tetracyclic product - converted to

chololesterol

Synthesis of isoprenoids and steroids

Synthesis of isopentenyl diphosphate

• Cytosol

• Substrate: AcCoA

• Intermediates: HMG-CoA (3-hydroxy-3-

methylglutaryl CoA) and mevalonate

• HMG-CoA reductase (forms

mevalonate from HMG-CoA) -

regulatory enzyme

β-ketothiolase

• The last step of β-oxidation - reverse

reaction

• 2 AcCoA → acetoacetyl~CoA

HMG-CoA synthase

Synthesis of isoprenoids and steroids

Cholesterol synthesis

HOHO

O P

O PPO PP O PP

P

Dimethylallyl diphosphate Isopentenyl diphosphate Geranyl diphosphate

farnesyl diphosphate

squalene

squalene lanosterol cholesterol

Regulation of cholesterol

synthesis

• Around 800 mg of cholesterol per day

(liver, intestine)

• The amount in diet varies ~ 300 mg

• Cellular cholesterol levels - feedback

regulation of the activity and the

amount of HMG-CoA reductase

Regulation of cholesterol

synthesis

• 1) Rate of reductase transcription:

transcription factor sterol regulatory

element binding protein (SREBP) -

low Chol level activates SREBP, high

inhibits

• 2) Rate of reductase translation:

inhibited by non-steroid metabolites

derived from mevalonate

Regulation of cholesterol

synthesis

• 3) Reductase degradation: high

concentrations of cholesterol start

proteolysis

• 4) Phosphorylation reduces the

activity of reductase: AMP-activated

protein kinase stops cholesterol

synthesis - no ATP → no Chol

Cholesterol synthesis inhibitors

• Statins (eg.

simvastatin,

lovastatin)

• Competitive

inhibitors (Ki = 1

nM) of HMG-CoA

reductase Lovastatin

CH3

CH3

CH3O

O

CH3

OH

OH

COO

H

-

Transport of lipids in plasma -

metabolism of lipoproteins

High molecular weight

compounds of blood plasma

• Lipoproteins

• Proteins

Transport of lipids in plasma

• Fatty acids

– Shorter FA (ut to 12C): freely

dissolved in plasma

– FA with longer chain: bound to

albumin

• Other lipids: transported by

lipoproteins

Lipoproteins

• Nonpolar core:

TAG a CE

• Surface

consists of:

• 1) phospholipids

• 2) apoproteins

• 3) cholesterol

Apoproteins - stabilization of particles

• 1) Structural Apo: Apo B100 and Apo

B48

• 2) Cofactors (activators) of enzymes:

Apo C-II (LPL) and Apo A-I (LCAT)

• 3) Receptor ligands: Apo B100 and

Apo E (for LDL-receptor), Apo E (for

scavenger receptor), Apo A-I (for HDL-

receptor)

Lipoproteins

• Different groups - density and apoproteins:

• 1) Chylomicrons: carry TAG and CE from intestine

to tissues

• 2) Very low density lipoproteins (VLDL): carry

newly synthesized TAG from liver to peripheral

tissues

• 3) Intermediary d. l. (IDL): formed from VLDL

• 4) Low d. l. (LDL): carry CE from liver to tissues

• 5) High d. l. (HDL): collect CE from tissues and

brings it to liver → bile acids → excretion

Chylomicrons

• Transport TAG and CE from intestine to

tissues

• First in lymph → through the thoracic duct to

blood

• Lipoprotein lipase (LPL) hydrolyzes TAG to

MAG and FA, FA penetrate to cells

• LPL has a cofactor: Apo C-II

• LPL action → chylomicron remnants (smaller,

more CE and MAG) → catched by hepatocytes

(receptor ligand is Apo E)

VLDL

• Formed in liver

• Transfer TAG produced in liver

• LPL converts VLDL to IDL

• CETP (cholesterol ester transport

protein): lipid exchange between HDL

and VLDL → from HDL to VLDL

transports CE, opposite direction TAG

→ more efficient lipid transport

Lipoprotein lipase (LPL)

• Endothelial cells (mainly in adipose

and muscle tissue)

• Hydrolyzes TAG in:

– 1) chylomicrons → chylomicron

remnants

– 2) VLDL → IDL

• Cofactor: Apo C-II

IDL

• From VLDL (LPL action)

• More CE and less TAG

• Their fate is finished in liver:

• 1) absorption and destruction

• 2) hepatic lipase (HL) hydrolyzes

TAG in IDL → only CE remain →

formation of LDL particles

LDL

• From IDL (HL) or de novo synthesis

• Contain CE → transport to tissues

• If the cell needs CE → expression of

LDL-receptors (rec. for Apo B100 and

Apo E)

• „Bad“ lipoprotein - atherogenic

• Plasma concentration should be below

3.0 mM, in diabetics below 2.5 mM

HDL

• Reverse cholesterol transport

from tissues to liver → excretion

• LCAT fills HDL with CE

• Formation in liver and enterocytes

as a flat empty discs - nascent HDL (only membrane, Apo A1, 2, 3 and ±

Apo C-II and Apo E)

LCAT

• Lecitin cholesterol acyltransferase

– donor – lecithin (phosphatidylcholine)

– acceptor – cholesterol

– transported particle – acyl

– transferase

– cofactor is Apo A-I

HDL

• Nascent HDL are filled with CE and

converted to HDL3 and HDL2α (varies in

cholesterol content - HDL3 has less)

• CETP (cholesterol ester transport

protein): lipid exchange between HDL

and VLDL → from HDL to VLDL

transports CE, in opposite direction TAG

• CETP activity transforms HDL2α to

HDL2β

HDL

• HDL2β to liver → same fate as IDL

• HL hydrolyzes TAG: HDL2β → HDL3

• HDL3 back to circulation

• Part of HDL is destroyed in liver →

excretion

HDL

• „Good“ lipoprotein - against

atherogenesis

• Plasma concentrations should be

higher than 1.0 mM in men and

higher than 1.2 mM in women

• Sex hormones protect women

before menopause from

atherosclerosis

Familial hypercholesterolemia

• Mutations in the gene for the LDL receptor

• Consequence: impaired uptake of LDL

particles → increased cholesterol

• Excess cholesterol is deposited in the

vessel wall → development of

atherosclerosis and its subsequent

complications (eg, myocardial infarction

or stroke) at a young age

Šlachové xantomy, xantelasma víček a

arcus lipoides corneae

Arcus lipoides corneae

Slit-lamp examination revealed a central collection of anterior stromal crystalline deposits

(arrowheads) and arcus lipoides (arrows) in the cornea. The patient's condition,

known as Schnyder's crystalline corneal dystrophy (SCCD), results from the

deposition of cholesterol and phospholipids in the corneal stroma, causing a

generalized corneal haze.

http://www.nejm.org/doi/full/10.1056/NEJMicm0911357