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Lipoprotein metabolism
Patarabutr Masaratana
Outline
Structure & Function
Classification
Metabolism
Atherosclerosis
Abnormalities
Blood protein
Plasma
Erythrocytes
Plasma proteinLipoprotein
Hemoglobin
conjugated protein: protein +
lipid
apolipoprotein + lipid
main function: lipid transport
transport of fat-soluble vitamins
Lipoproteins
lipid transport
- lipid: triglyceride
cholesterol
phospholipid
cholesteryl ester (CE)
- protein: apolipoprotein (apo)
enzymes
Components of lipoprotein particles
Components of lipoprotein particles
most lipoprotein particles: spherical
shape
core: hydrophobic molecules
surface (shell): hydrophilic/amphipathic
molecules
Structure of lipoproteins
triglyceride (TG)CE
cholesterolphospholipid
apo
Structure of lipoproteins
Classification of lipoproteins
diversity in size, density, lipid & protein components and electrophoretic movement
high TG content bigger particle core
larger particle size
increased lipid contentrelative to protein
lower density
Classification of lipoproteins
diversity in size, density, lipid & protein components and electrophoretic movement
low TG content higher density
Classification of lipoproteins
high density lipoprotein (HDL)
low density lipoprotein (LDL)
intermediate density lipoprotein (IDL)
very low density lipoprotein (VLDL)
chylomicron
Classification of lipoproteins
Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:3145-3161.
TG content
lowest
highest
Classification of lipoproteins
Agarose gel electrophoresis
chylomicron (origin)
HDL LDL
VLDL (pre-β)
Classification of lipoproteins
chylomicron VLDL LDL HDL
Main components
Main apo
% Lipid
- TG
- cholesterol
% Protein
TG(from diet)
B48
98
84
7
2
TG(endogeno
us)
B100
89-96
44-60
16-22
4-11
CE
B100
77
11
62
23
Protein
AI
50
3
19
50
scaffold for lipation
ligands for lipoprotein receptors
activators/inhibitors of enzymes
involving in lipoprotein metabolism
General functions of apolipoproteins
1. Exogenous pathway
2. Endogenous pathway
3. Reverse cholesterol transport
Overview of lipoprotein metabolism
chylomicronapo B-48
Exogenous pathway
Overview of lipoprotein metabolism
direction of major lipid transport
- ขนส่�ง TG ในอาหารไปยั�ง muscle, adipose tissue
- ลำ�าไส่�เลำ�ก- fatty acid ถู�กส่�งเคราะห�กลำ�บเป�น
TG อ�กคร��ง - cholesterol ถู�ก esterify เป�น
CE
- TG รวมก�บ CE, apo B-48 แลำะ phospholipid เป�น chylomicron
- เข�าส่��ร�างกายัทาง lacteal
thoracic duct
- TG ถู�กส่ลำายัได้� fatty acid เข�าส่�� peripheral cells
- CE, phospholipid ถู�กส่�งไปท�$ตั�บ
VLDL-IDL-LDLapo B-100
Overview of lipoprotein metabolism
direction of major lipid transport
Endogenous pathway- ขนส่�ง endogenous TG จากตั�บ
ไปยั�ง muscle, adipose
tissue
- TG ในตั�บรวมก�บ CE, apo B-
100 แลำะ phospholipid เป�น VLDL แลำ�วหลำ�$งเข�าส่�� circulation
- TG ถู�กส่ลำายัได้� fatty acid เข�าส่�� peripheral cells
- CE บางส่�วนอาจเข�าส่�� peripheral
cells
- VLDL เส่�ยั TG จ'งม�ขนาด้เลำ�กลำง กลำายัเป�น IDL แลำะ LDL ตัามลำ�าด้�บ
- CE, phospholipid ถู�กส่�งกลำ�บไปท�$ตั�บ
HDLapo A-I
Overview of lipoprotein metabolism
direction of major lipid transport
Reverse cholesterol transport- ขนส่�งไขม�นในท(ศทางตัรงข�ามก�บ
exogenous แลำะ endogenous
pathway
- ตั�บส่�งเคราะห� apo A-I
- apo A-I รวมก�บ phospholipid
เก(ด้เป�น nascent HDL (discoidal
shape)
- nascent HDL ได้�ร�บ cholesterol
จาก peripheral cells
- cholesterol ท�$ nascent HDL ได้�ร�บ ถู�ก esterify เป�น CE ซึ่'$งจะยั�ายัไปอยั��ใน core ของ HDL
- HDL ม�ขนาด้ใหญ่�ข'�น แลำะเปลำ�$ยันร�ปร�างเป�น spherical shape (mature
HDL)
Reverse cholesterol transport (HDL; apo A-I)
apolipoprotein
- nontransferable- transferable
Overview of lipoprotein metabolism
Endogenous pathway (VLDL-IDL-LDL; apo B-100)
Exogenous pathway (chylomicron; apo B-48)
apo C, apo E
Lipoprotein lipase (LPL) - อยั��บนผิ(ว endothelium ของหลำอด้เลำ-อด้ฝอยัในอว�ยัวะตั�างๆ เช่�น กลำ�ามเน-�อลำายั, ห�วใจ, เน-�อเยั-$อไขม�น
- ถู�กกระตั1�นการท�างานโด้ยั apo C-II
- LPL ส่ลำายั TG ท�$ core ของ chylomicron, VLDL ได้� free fatty acid เข�าส่��เซึ่ลำลำ�กลำ�ามเน-�อแลำะ adipocyte
- chylomicron แลำะ VLDL ส่�ญ่เส่�ยั TG ท�$ core ของอณู� ท�าให�ม�ขนาด้เลำ�กลำง กลำายัเป�น chylomicron remnant, IDL ตัามลำ�าด้�บ
- chylomicron remnant แลำะ IDL ถู�กน�าเข�าส่��ตั�บ
- TG ใน IDL บางส่�วน จะถู�กส่ลำายัเพิ่($มเตั(มอ�ก ท�าให� IDL ม�ขนาด้เลำ�กลำงอ�ก กลำายัเป�น LDL
- LDL ถู�กน�าเข�าส่��ตั�บ หร-อ peripheral cells
Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:3145-3161.
Lipid absorption
lipid digestion: pancreatic lipase, bile
acid
medium-chain fatty acid: directly enter
the blood and transported by albumin
long-chain fatty acid: resynthesised to
TG packaged into chylomicron (apo B-
48) & released into lymphatic system
Exogenous pathway
chylomicron acquires apo C & apo E from HDL
in the blood
apo C-II activates LPL hydrolysis of TG in
chylomicron free fatty acid (FFA)
FFA enters myocyte or adipocyte β-
oxidation or lipogenesis
chylomicron loses core TG becomes smaller
(chylomicron remnant) exposure of apo E
on particle surface (release apo C back to
HDL)
apo E-mediated chylomicron uptake into liver
through LDL receptor or LRP (LDL receptor-
related protein)
Exogenous pathway
chylomicron
HDL
apo Capo E
chylomicron remnant
Lipolysis of core TG
LPLapo C-II
FFA
β-o
xid
ati
on
lipog
en
esis
apo
C
LDL receptorLDL receptor-related protein (LRP)
apo E
Exogenous pathway
chylomicron: half life = 10 minutes
not normally found in serum after 12-
hour fasting
chylomicron: large particle light
reflection
milky serum (lipemia)
(also caused by VLDL in serum)
postprandial lipemia OR patients with
abnormal chylomicron metabolism
LPL
apo E
apo C-II
chylomicron
chylomicron remnant
Endogenous pathway
Sources of endogenous TG
1. de novo lipogenesis
(e.g. from excess dietary carbohydrate)
2. cytosolic TG storage in hepatocytes
3. fatty acids acquired from lipoproteins
delivered to the liver
4. FFA delivered to the liver
depend on metabolic states
Tamura S. and Shimomura I. J Clin Invest. 2005;115(5):1139–1142.
Endogenous pathway
endogenous TG + CE + phospholipid + apo
B-100 VLDL released into circulation
acquires apo C & apo E from circulating HDL
apo C-II activates LPL hydrolysis of TG in
VLDL free fatty acid (FFA)
FFA enters myocyte or adipocyte β-
oxidation or lipogenesis
VLDL loses core TG becomes smaller (IDL)
release apo C, phospholipid to HDL
Endogenous pathway
endogenous TGCEphospholipidapo B-100
VLDL
HDLapo C
apo E
Lipolysis of core TG
LPLapo C-II
IDL
FFA
β-o
xid
ati
on
lipog
en
esis
apo Cphospholipid
Endogenous pathwayIDL
IDL
LDL receptor/LRP
50%
apo E
50%
Further lipolysis by hepatic TG lipase (HTGL)
LDL
HDL
apo Capo E
apo B-100
Scavenger receptor B type I(SR-BI)
Receptor-mediated endocytosis of LDL
LDL receptor
LPL
apo-B100
apo E
apo C-II
chylomicron remnant
VLDL
IDL
LDL
Reverse cholesterol transport
apo A-I nascent HDL
chylomicron, VLDL, IDL (through lipolysis)
apo C, apo Ephospholipid
mature HDL(HDL3)
cholesterol
CE
LCAT apo A-I
mature HDL(HDL2)
VLDL
chylomicron
CETP
ABCA1SR-BI
aqueousdiffusion
CEapo C, apo E
TG
LCAT: lecithin-cholesterol acyltransferase CETP: cholesteryl ester transfer proteinABCA1: ATP-binding cassette transporter
A1
Reverse cholesterol transport
mature HDL(HDL2)
lipolysis by hepatic TG lipase (HTGL)
nascent HDL
another cycle of reverse cholesterol transport
FFA
SR-BI(liver)
CE
LDL receptor (apo E)LRP (apo E)
other unknown receptors
Reverse cholesterol transport
HDL
LDL receptor
LPL
apo-B100
apo E
apo C-II
chylomicron
chylomicron remnant
VLDL
IDL
LDL
HDL
Cholesterol & Atherosclerosis
endothelial dysfunction(functional structural)
increased endothelial permeability to lipoproteins
lipid deposition in intimaesp. small lipoproteins
LDL
oxidized LDL
inflammatory processes ROS
foam cells macrophages
scavenger receptor
No feedback regulation
smoking, hypertension, diabetes, etc
Cholesterol & Atherosclerosis
Cholesterol & Atherosclerosis
Cholesterol & Atherosclerosis
antiathergonic properties of HDL: reverse cholesterol transport
antioxidant- prevent LDL oxidation
The National Cholesterol Education Program (NCEP)
NCEP Adult Treatment Panel (ATP)
ATP III, ATP IV (due 2012)
Adult reference ranges for lipids
Reference range (mg/dL)
Total
cholesterol
140-200
HDL
cholesterol
40-75
LDL
cholesterol
50-130
TG 60-150
LDL cholesterol calculation (Friedewald formula)
LDL-C = Total cholesterol – HDL-C – (TG/5)
not valid if TG > 400
LDL + HDL + VLDL
dyslipidemia: abnormal lipid levels
causes: defective
synthesis/transport/catabolism of lipoproteins
hyperlipoproteinemia: elevated lipoprotein
levels
- hypercholesterolemia
- hypertriglyceridemia
- combined hyperlipidemia
hypolipoproteinemia: decreased lipoprotein
levels
Abnormalities of lipid metabolism
Monogenic disorders
Polygenic disorders
Multifactorial: Genetics + Environment
Hyperlipoproteinemia
isolated high plasma cholesterol
concentration
Common hypercholesterolaemia
- most frequent dyslipidemia,
multifactorial
Familial hypercholesterolemia (FH)
- LDL receptor gene mutations
Familial defective apo B-100
- apo B-100 gene mutations defective
LDL receptor binding
Autosomal recessive hypercholesterolemia
- mutations defective LDL receptor-
mediated endocytosis
Hypercholesterolemia
monogenic disorder, autosomal dominant,
rare
LDL receptor gene mutations
very high plasma cholesterol & LDL-C
levels
premature CHD (teenage years)
lipid deposits at eyelids, tendon, hand,
cornea
heterozygotes: also symptomatic, develop
CHD at the age of 20s-50s
Familial hypercholesterolemia
LDL receptor
LPL
apo-B100
apo E
apo C-II
chylomicron
chylomicron remnant
VLDL
IDL
LDL
isolated high plasma TG concentration
borderline high: 150-200 mg/dL
high: 200-500 mg/dL
very high: >500 mg/dL
genetic abnormalities or secondary
causes
(e.g. some hormonal abnormalities)
imbalance between VLDL synthesis vs
clearance
Hypertriglyceridemia
Familial chylomiconemia
- very rare; LPL or apo C-II deficiency
- chylomicron & VLDL accumulation very
high TG
- fasting chylomicronaemia
Familial hypertriglyceridemia
- relatively common
- isolated VLDL elevation
- excess VLDL production
- still largely unknown molecular basis but
likely polygenic & requires secondary
factor for expression
Hypertriglyceridemia
LDL receptor
LPL
apo-B100
apo E
apo C-II
chylomicron
chylomicron remnant
VLDL
IDL
LDL
Fig. 1: Clinical manifestations of primary hypertriglyceridemia.
Yuan G et al. CMAJ 2007;176:1113-1120
©2007 by Canadian Medical Association
elevated total cholesterol & TG levels
Familial combined hyperlipidemia (FCH)
- autosomal dominant with variable
penetrance
- overproduction of apo B-100
- increased VLDL production & subsequent
LDL generation
- variable lipid profiles
Combined hyperlipidemia
Familial dysbetaipoproteinemia
- apo E gene mutations apo E isoforms
with low affinity to LDL receptor
- IDL & chylomicron remnant
accumulation
- defective catabolism
- phenotypic expression usually requires
accompanying factors e.g. obesity, type
2 DM
Combined hyperlipidemia
LDL receptor
LPL
apo-B100
apo E
apo C-II
chylomicron
chylomicron remnant
VLDL
IDL
LDL
Molecular basis
Clinical descriptive names
Fredrickson system (old literatures)
Classification of Primary hyperlipoproteinemia
57
Type I Type II A Type II B Type III Type IV Type V
Prevalence very rare
most common very rare very common
rare
Serum analysis- Cholesterol- Triglyceride
N or N
N or
LP pattern-Chylomicron-VLDL-LDL
chylomicron remnant
IDL
Serum appearance- Cream layer- Turbidity
++++0
00
0
±0 or +
+0
++++
+++
Cause LPLdefect
no or abn.LDL
receptor
LDL cat. VLDL
syn.
abn. apo E CHO intake
severe degree of
type V
Fredrickson classification for Primary hyperlipoproteinemia
1 2 3 4 5 6
Chylomicronemia & Lipemia?
high TG lipemia
high chylomicron or chylomicron remnant or VLDL levels
plasma protein electrophoresis
Standing plasma test(refrigeration test) chylomicron,
chylomicron remnant
VLDL(unchanged)
cream layer
Stored at 4° overnight
Standing plasma test
Obesity, metabolic syndrome, diabetes
- DM: increased glucose shunt into PPP
increased fatty acid synthesis
- increased VLDL concentrations
- deficient LPL activity, increased CETP
activity
- increased FFA flux to the liver
- fatty liver
Alcohol
- increased VLDL concentrations
- impaired lipolysis
Secondary hypertriglyceridemia
Hormone-sensitive lipase
EpinephrineNorepinephrineGrowth hormone
ACTHThyrotropin
increased serum TG levels
triglyceride
LDL receptor
LPL
apo-B100
apo E
apo C-IIDM
obesityalcohol
FCHDM
Mechanisms of dyslipidemia: General concept
chylomicron
chylomicron remnant
VLDL
IDL
LDL
Downloaded from: StudentConsult (on 14 August 2012 02:37 PM)
© 2005 Elsevier
Transport and storage of fat in response to feeding
Metabolism in the fed (postprandial) state
Metabolism in postabsorptive state
Metabolism in prolonged fasting state
decreased lipoprotien concentrations
1. hypoalphalipoproteinaemia
- isolated decrease in HDL levels (<40 mg/dL)
- without hypertriglyceridaemia
- often caused by genetic defects
(e.g. apo A-I or LCAT deficiency, ABCA1 mutations)
- increased risk of premature CHD
- severe physiological stress acute transient change
2. hypobetalipoproteinaemia
- isolated low levels of LDL (apo B-100 mutations)
- no accompanying lipoprotein disorders
3. abetalipoproteinaemia: very rare, caused by defective
VLDL assembly
Hypolipoproteinaemia
Statins
- HMG-Co A reductase inhibitor
- suppress cholesterol synthesis
- increase LDL receptor expression
Fibrates
- LPL stimulation
Main lipid-lowering medications
