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-3methylglutaryl 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
O P P
Dimethylallyl diphosphate
O P P
O P P
Isopentenyl diphosphate
Geranyl diphosphate
O P
P
farnesyl diphosphate
squalene
HO
squalene
HO
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
HO
COO
-
OH
H3C
O
H
O
Lovastatin
CH3
H3C
CH3
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 HDLreceptor)
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