Transcript chylomicron remnant

Lipoprotein metabolism
Patarabutr Masaratana
Outline

Structure & Function

Classification

Metabolism

Atherosclerosis

Abnormalities
Blood protein
Plasma
Erythrocytes
Plasma protein
Lipoprotein
Hemoglobin
Lipoproteins

conjugated protein: protein + lipid

apolipoprotein + lipid

main function: lipid transport

transport of fat-soluble vitamins
Components of lipoprotein particles
lipid transport
-
lipid: triglyceride
cholesterol
phospholipid
cholesteryl ester (CE)
-
protein: apolipoprotein (apo)
enzymes
Components of lipoprotein particles
Structure of lipoproteins

most lipoprotein particles: spherical shape

core: hydrophobic molecules
triglyceride (TG)
CE

surface (shell): hydrophilic/amphipathic molecules
cholesterol
phospholipid
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 content
relative 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
highest
lowest
TG content
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.
Classification of lipoproteins
Agarose gel electrophoresis
VLDL (pre-β)
HDL
LDL
chylomicron (origin)
Classification of lipoproteins
chylomicron
VLDL
LDL
HDL
TG
(from diet)
TG
(endogenous)
CE
Protein
B48
B100
B100
AI
% Lipid
98
89-96
77
50
- TG
84
44-60
11
3
- cholesterol
7
16-22
62
19
2
4-11
23
50
Main
components
Main apo
% Protein
General functions of apolipoproteins

scaffold for lipation

ligands for lipoprotein receptors

activators/inhibitors of enzymes involving in
lipoprotein metabolism
Overview of lipoprotein metabolism
1. Exogenous pathway
2. Endogenous pathway
3. Reverse cholesterol transport
Overview of lipoprotein metabolism
Exogenous pathway
-
ขนส่ง TG ในอาหารไปยัง muscle,
adipose tissue
-
chylomicron
apo B-48
ลาไส้เล็ก
- fatty acid ถูกสังเคราะห์กลับเป็ น
TG อีกครัง้
- cholesterol ถูก esterify เป็ น CE
- TG รวมกับ CE, apo B-48 และ
phospholipid เป็ น chylomicron
-
direction of major lipid transport
เข้าสู่ร่างกายทาง lacteal 
thoracic duct
Overview of lipoprotein metabolism
Endogenous pathway
-
ขนส่ง
endogenous TG จากตับไป
ยัง muscle, adipose tissue
- TG ในตับรวมกับ CE, apo B-100
และ phospholipid เป็ น VLDL
แล้วหลังเข้
่ าสู่ circulation
VLDL-IDL-LDL
apo B-100
- TG ถูกสลายได้ fatty acid เข้าสู่
peripheral cells
- CE บางส่วนอาจเข้าสู่ peripheral
cells
direction of major lipid transport
- VLDL เสีย TG จึงมีขนาดเล็กลง
Overview of lipoprotein metabolism
Reverse cholesterol transport
-
ขนส่งไขมันในทิศทางตรงข้ามกับ
exogenous และ endogenous
pathway
-
ตับสังเคราะห์ apo A-I
- apo A-I รวมกับ phospholipid เกิดเป็ น
HDL
apo A-I
nascent HDL (discoidal shape)
- nascent HDL ได้รบ
ั cholesterol จาก
peripheral cells
- cholesterol ที่ nascent HDL ได้รบ
ั ถูก
direction of major lipid transport
esterify เป็ น CE ซึ่งจะย้ายไปอยู่ใน
Overview of lipoprotein metabolism
apolipoprotein
- nontransferable
- transferable
Exogenous pathway (chylomicron; apo B-48)
Endogenous pathway (VLDL-IDL-LDL; apo B-100)
apo C, apo E
Reverse cholesterol transport (HDL; apo A-I)
Lipoprotein lipase (LPL)
-
-
อยู่บนผิว endothelium ของ
หลอดเลือดฝอยในอวัยวะต่างๆ
เช่น กล้ามเนื้ อลาย, หัวใจ,
เนื้ อเยื่อไขมัน
ถูกกระตุ้นการทางานโดย apo CII
- LPL สลาย TG ที่ core ของ
chylomicron, VLDL ได้ free
fatty acid เข้าสู่เซลล์กล้ามเนื้ อ
-
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.
และ adipocyte
chylomicron และ VLDL สูญเสีย
TG ที่ core ของอณู ทาให้มีขนาด
เล็กลง กลายเป็ น chylomicron
remnant, IDL ตามลาดับ
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
Lipolysis of core TG
apo C-II
LPL
chylomicron
apo C
apo E
β-oxidation
FFA
lipogenesis
HDL
chylomicron remnant
apo E
LDL receptor
LDL receptor-related protein (LRP)
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
chylomicron
apo C-II
LPL
apo E
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 TG
CE
phospholipid
apo B-100
HDL
VLDL
apo C
phospholipid
Lipolysis of core TG
LPL
FFA
lipogenesis
IDL
β-oxidation
apo C-II
Endogenous pathway
IDL
IDL
Further lipolysis by
hepatic TG lipase (HTGL)
apo E
HDL
apo C
apo E
LDL
LDL receptor/LRP
apo B-100
Scavenger receptor B type I
(SR-BI)
Receptor-mediated endocytosis of LDL
VLDL
apo C-II
LPL
apo E
IDL
chylomicron remnant
apo-B100
LDL
LDL receptor
Reverse cholesterol transport
nascent HDL
apo A-I
apo C, apo E
phospholipid
chylomicron, VLDL, IDL
(through lipolysis)
cholesterol
LCAT
ABCA1 aqueous
SR-BI diffusion
apo A-I
CE
mature HDL
(HDL3)
VLDL
chylomicron
TG
CETP
CE
apo C, apo E
mature HDL
(HDL2)
LCAT: lecithin-cholesterol acyltransferase
CETP: cholesteryl ester transfer protein
ABCA1: ATP-binding cassette transporter A1
Reverse cholesterol transport
mature HDL
(HDL2)
lipolysis by
hepatic TG lipase (HTGL)
SR-BI
(liver)
FFA
nascent HDL
another cycle of
reverse cholesterol transport
CE
LDL receptor (apo E)
LRP (apo E)
other unknown receptors
Reverse cholesterol transport
HDL
chylomicron
VLDL
apo C-II
LPL
HDL
apo E
IDL
chylomicron remnant
apo-B100
LDL
LDL receptor
Cholesterol & Atherosclerosis
endothelial dysfunction
(functional  structural)
increased endothelial
permeability to lipoproteins
smoking, hypertension, diabetes, etc
lipid deposition in intima
esp. small lipoproteins
LDL
inflammatory processes  ROS
oxidized LDL
scavenger receptor
foam cells
macrophages
No feedback regulation
Cholesterol & Atherosclerosis
Cholesterol & Atherosclerosis
Cholesterol & Atherosclerosis
antiathergonic properties of HDL: reverse cholesterol transport
antioxidant- prevent LDL oxidation
Adult reference ranges for lipids
Reference range (mg/dL)
LDL + HDL + VLDL
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
The National Cholesterol Education Program (NCEP)
NCEP Adult Treatment Panel (ATP)
ATP III, ATP IV (due 2012)
Abnormalities of lipid metabolism

dyslipidemia: abnormal lipid levels

causes: defective synthesis/transport/catabolism of
lipoproteins

hyperlipoproteinemia: elevated lipoprotein levels
- hypercholesterolemia
- hypertriglyceridemia
- combined hyperlipidemia

hypolipoproteinemia: decreased lipoprotein levels
Hyperlipoproteinemia

Monogenic disorders

Polygenic disorders

Multifactorial: Genetics + Environment
Hypercholesterolemia

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
Familial 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
chylomicron
VLDL
apo C-II
LPL
IDL
apo E
chylomicron remnant
apo-B100
LDL
LDL receptor
Hypertriglyceridemia

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
chylomicron
VLDL
apo C-II
LPL
IDL
apo E
chylomicron remnant
apo-B100
LDL
LDL receptor
Fig. 1: Clinical manifestations of primary hypertriglyceridemia.
Yuan G et al. CMAJ 2007;176:1113-1120
©2007 by Canadian Medical Association
Combined hyperlipidemia

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
chylomicron
VLDL
apo C-II
LPL
IDL
apo E
chylomicron remnant
apo-B100
LDL
LDL receptor
Classification of Primary hyperlipoproteinemia

Molecular basis

Clinical descriptive names

Fredrickson system (old literatures)
Fredrickson classification for Primary hyperlipoproteinemia
Type I
Prevalence
Serum analysis
- Cholesterol
- Triglyceride
very
rare
Type II A
Type II B
most common
Type III
Type IV
Type V
very rare
very
common
rare
N or
N or
N
LP pattern
-Chylomicron
-VLDL
-LDL
chylomicron
remnant
IDL
Serum
appearance
- Cream layer
- Turbidity
++++
0
0
0
Cause
1 2 3 4 5 6
LPL
defect
no or abn.
LDL
receptor
0
±
0 or +
+
LDL cat. abn. apo E
VLDL
syn.
0
++
++
+++
CHO
intake
severe
degree of
type V
57
Chylomicronemia & Lipemia?

high TG  lipemia

high chylomicron or
chylomicron remnant
or VLDL levels

plasma protein
electrophoresis

Standing plasma test
(refrigeration test)
Stored at 4° overnight
cream
layer
chylomicron,
VLDL
chylomicron remnant (unchanged)
Standing plasma test
Secondary hypertriglyceridemia

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
Epinephrine
Norepinephrine
Growth hormone
ACTH
Thyrotropin
Hormone-sensitive lipase
increased serum TG levels
triglyceride
Mechanisms of dyslipidemia: General concept
chylomicron
DM
obesity
alcohol
FCH
VLDL
apo C-II
LPL
DM
IDL
apo E
chylomicron remnant
apo-B100
LDL
LDL receptor
Transport and storage of fat in response to feeding
Downloaded from: StudentConsult (on 14 August 2012 02:37 PM)
© 2005 Elsevier
Metabolism in the fed (postprandial) state
Metabolism in postabsorptive state
Metabolism in prolonged fasting state
Hypolipoproteinaemia
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
Main lipid-lowering medications

Statins
- HMG-Co A reductase inhibitor
- suppress cholesterol synthesis
- increase LDL receptor expression

Fibrates
- LPL stimulation