Aula 20

- Metabolismo das lipoproteínas.

Lipoproteínas são complexos de proteínas e lípidos de
elevado peso molecular com funções de transporte de lípidos na
corrente sanguínea.

Dividem-se em:
- Quilomicra
- VLDL (do inglês: Very Low Density Lipoproteins)
- LDL (do inglês: Low Density Lipoproteins)
- IDL (do inglês: Intermediate Density Lipoproteins)
- HDL (do inglês: High Density Lipoproteins)
Propriedades das lipoproteínas plasmáticas.

Lipoproteínas Densidade Lipidos Mobilidade Apoproteínas

(g/ml) electroforética

QM < 0,94 TG α B48; AI, IV

VLDL 0,94 a 1,006 TG Pre-β B100, E,

CI, II, III
IDL 1,006 a 1,019 TG e EC Pre-β B100, E

LDL 1,019 a 1,063 EC β B100

HDL 1,063 a 1,21 FL e Col α AI, II

Composição média em lipidos e proteínas das lipoproteínas
plasmáticas (% em peso seco).

Componente Quilomicra VLDL IDL LDL HDL

Proteína 2 9 20 21 50

VLDL 84 54 19 11 4

IDL 2 7 8 8 2

LDL 5 12 27 37 20

HDL 7 18 21 22 24
Esquema de uma lipoproteína.
 Apolipoproteínas
- Apo AI (fígado, intestino delgado)
Estrutural, activador da lecitina colesterol acil transferase (LCAT)
- Apo AII (fígado)
Estrutural; inibidor da lipase hepática; componente de ligandos
para a ligação às HDL
- Apo AIV (intestino delgado)
Activador da LCAT, modulador da lipoproteína lipase (LPL)
- Apo B-100 (fígado)
Estrutural, síntese das VLDL; ligando para o receptor das LDL
- Apo B-48 (intestino delgado)
Estrutural, síntese das quilomicra; ligando para o receptor das
LDL; derivada do mRNA da apo B-100
- Apo E (fígado, macrofagos, cérebro)
Ligando para o receptor da apo E; mobilização do colesterol celular
 Apolipoproteínas (continuação)
- Apo C-I (fígado)
Activador da LCAT
- Apo C-II (fígado)
Activador da LPL
- Apo C-III (fígado)
Inibidor da LPL
 Metabolismo das Lipoproteinas

• Exogenous/chylomicron pathway (dietary fat)

• Endogenous pathway (lipids synthesized by
the liver)
• HDL metabolism (apolipoprotein transfer,
cholesteryl ester transfer, reverse cholesterol
transport
 Metabolismo das Lipoproteinas

• Exogenous/chylomicron pathway (dietary fat)

• Endogenous pathway (lipids synthesized by
the liver)
• HDL metabolism (apolipoprotein transfer,
cholesteryl ester transfer, reverse cholesterol
transport
TG Rich: Chylomicrons
Surface Monolayer
Phospholipids (5%)
Free Cholesterol (1%)
Protein (1%)

Hydrophobic Core
Triglyceride (93%)
Cholesteryl Esters (1%)
 Chylomicron
Metabolism
Long-chain fatty acids
are re-esterified into
triacylglycerols in the gut
and transferred;
chylomicrons which
contain apoB48 are
synthesized and
secreted into the blood
via the lymphatic
circulation
 Chylomicron
Metabolism
ApoC’s, apoE and
cholesteryl esters are
acquired from HDL in
circulation.

ApoA-I and apoA-IV may

be acquired from either the
intestine or from HDL in
circulation.
 Chylomicron
Metabolism
ApoC-II activates
lipoprotein lipase which
catalyses the hydrolysis
of triacylglycerols
Chylomicron
Metabolism
Apolipoproteins are
transferred back to HDL
Chylomicron
Metabolism
The chylomicron
remnant is taken up by
the apoB48/remnant
receptor in the liver
 Metabolismo das Lipoproteinas

• Exogenous/chylomicron pathway (dietary fat)

• Endogenous pathway (lipids synthesized by
the liver)
• HDL metabolism (apolipoprotein transfer,
cholesteryl ester transfer, reverse cholesterol
transport
TG Rich: VLDL
Surface Monolayer
Phospholipids (12%)
Free Cholesterol (14%)
Protein (4%)

Hydrophobic Core
Triglyceride (65%)
Cholesteryl Esters (8%)
 Biossíntese dasVLDL

Microsomal
TG transfer Facilitates the
protein (MTP) translocation, folding
of apoB and addition TG and
of lipids to lipid cholesterol are
binding domains synthesized in
the liver as
VLDL which
contains apoB-
100
 VLDL
Metabolism

Apo C’s and apoE and

cholesteryl ester are
acquired from HDL in
circulation
 Fatty Acid Transport

ApoC-II activates
lipoprotein lipase which
catalyses the hydrolysis
of TG
 VLDL
Metabolism

Apolipoproteins are
transferred back to HDL

The end product is a

VLDL remnant (IDL)
 VLDL Remnant
Uptake

The remnant particle (IDL),

if it contains apoE, can be
taken up by the
apoE/remanant receptor
VLDL Conversion
to LDL
Further action on IDL by
hepatic lipase loses
additional apolipoproteins
(apoE) becomes and is
converted to LDL
CE Rich: LDL
Surface Monolayer
Phospholipids (25%)
Free Cholesterol (15%)
Protein (22%)

Hydrophobic Core
Triglyceride (5%)
Cholesteryl Esters (35%)
 LDL Metabolism

LDL is removed by
apoB100 receptors
which are mainly
expressed in the
liver

Hepatic Lipase
Cholesteryl ester
transfer protein
 LDL Uptake by Tissues

X X
Defects in the LDL receptor leads to familial hypercholesterolemia
 Metabolismo das Lipoproteinas

• Exogenous/chylomicron pathway (dietary fat)

• Endogenous pathway (lipids synthesized by
the liver)
• HDL metabolism (apolipoprotein transfer,
cholesteryl ester transfer, reverse cholesterol
transport
CE Rich: HDL
Surface Monolayer
Phospholipids (25%)
Free Cholesterol (7%)
Protein (45%)

Hydrophobic Core
Triglyceride (5%)
Cholesteryl Esters (18%)
 HDL Subpopulations
Particle Shape Apolipoprotein Composition
Discoidal

Spherical
A-I HDL A-I/A-II A-II HDL
HDL

Particle Size Lipid Composition

TG, CE, and PL

HDL2b HDL2a HDL3a HDL3b HDL3c

Rye KA et al. Atherosclerosis 1999;145:227-238.
 HDL Maturation
HDL is secreted in a
discoidal form from the liver
and gut.

As it acquires cholesterol
from tissues in the
circulation, it matures into a
spherical form through the
action of lecithin:cholesterol
acyl transferase
 HDL Metabolism
Nascent HDL (lipid-poor apoA-I) is produced by the liver and intestine
 HDL Metabolism
Free cholesterol is acquired from peripheral tissues
 HDL Metabolism
LCAT converts free cholesterol to cholesteryl esters
 HDL Metabolism
A variety of enzymes interconvert HDL subspecies
HDL Interconversions
HDL Interconversions
 HDL Metabolism
Cholesteryl esters can be selectively taken up via SR-BI
HDL particles can be taken up by a receptor-mediated process
 HDL Metabolism
Lipid-poor apoA-I can be removed by the kidney
Metabolismo Hepático Colesterol
 LDL Cellular Metabolism
LDL are taken up by the LDL Receptor into clathrin-coated pits
 LDL Cellular Metabolism
LDL dissociates from the receptor; the receptor recycles to the membrane
 LDL Cellular Metabolism
In the lysosome, lipids are deseterified; proteins are hydrolyzed
 LDL Cellular Metabolism
Increase in free cholesterol regulates decrease cholesterol synthesis
and uptake; increase cholesterol esterification
Aterogénese
Mecanismo de formação da placa