Lipoprotein metabolism Patarabutr Masaratana. Outline Structure & Function Classification ...

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