Lipoprotein metabolismSyed Shariq Naeem

Outline

• Introduction – Structure and Function• Apoproteins• Chylomicron Metabolism• VLDL, IDL & LDL Metabolism• HDL & Reverse cholesterol transport• Targets for Treating Dyslipidemia

CORECHOLESTEROL

ESTERS

TRIGLYCERIDES

MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL

INTEGRAL APOPROTEINS

PERIPHERAL APOPROTEINS

Structure of lipoprotein

Nomenclature of lipoproteinsDiameter

nmProtein

%Triglycerides

%Cholesteryl esters %

Chylomicron 75-1200 1 88 3

VLDL 30-80 10 56 15

IDL 25-30 10 29 34

LDL 18-25 ~20 13 48

HDL 5-12 ~50 13 30

Albumin Fatty acid complex

Lipoproteins Lipoprotein Apoproteins Function

Chylomicron apoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissues

VLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles.

IDL apoB-48, apoC, apoE Intermediary between VLDL and LDL

LDL apoB-48 Transport cholesterol to peripheral tissues.

HDL apoA, apoC, apoE, apoD

•Absorb cholesterol form peripheral tissues and transport it to liver•Reservoir for exchange of lipoproteins in VLDL and Chylomicron metabolism

Apoproteins:o Regulate the metabolism

of lipoproteins by modulating the activity of enzymes

oMediate the receptor mediated uptake of lipoproteins

Two kinds1. Integral proteins :

• Apo-A• Apo-B (B-48 &B-100)

2. Peripheral proteins:• Apo- C• Apo- E

Name Lipoprotein Function

apoA-I HDL, Nascent chylomicrons

Activates LCATStructural

apoA-II HDL, Nascent chylomicrons

Structural

Name Lipoprotein Function

apoB-100 VLDL, IDL, LDL StructuralSynthesis and secretion of VLDLBinds to LDL Receptor

ApoB-48(RNA EDITING)

Chylomicrons, Chylomicron remnant

StructuralSynthesis and secretion ofChylomicrons

Name Lipoprotein Function

apoC-I HDL, VLDL, IDL Chylomicrons

Activator of LCAT

apoC-II ChylomicronsHDL, VLDL, IDL

Activator of Lipoprotein lipase (LPL)

apoC-III ChylomicronsHDL, VLDL, IDL

Stabilizes surface

Name Lipoprotein Function

apoE HDL, VLDL, IDLChylomicrons

Binds to receptor on the cell membrane of liver

apoD HDL, Chylomicrons nascent

Cholestreyl ester exchange

Cholesterol biosynthesis

Exogenous PathwayChylomicron Processing

Duodenum

Fat

CCK

Bile salts

Micelles

Enterocytes

ACAT

Lacteal Thoracic duct Systemic circulation

apo B-48

apo-Capo-E

Chylomicron

Liver

Chylomicron

apo-B-48

apo-E

apo-C

Adipocyte

Chylomicron remnant

When TGs < 20% remaining, they loose apoC

apoE

VLDL

LDL-R Chylomicron remnant receptor

Endogenous PathwayVLDL Synthesis and Processing

Conversion of VLDL to LDLLDL Uptake

Liver

apo-B-100

TGs <50%

TGs <30%

VLDL Remnant

IDL

TGs < 10% Loses apoE & apoC

LDL

LDL-R

apo-B-100

Cell wall Aldosterone

CortisolSex hormones

apoB-100

VLDL

HDL

VLDL

LPL

Adipocyte &Myocyte

Remains attached to LPL

Hepatic uptake of Remnant Particles

CM OR VLDLREMNANT

HSPG

HEPATIC LIPASE

Sequestration

Lipolysis

Uptake

LDL-R LRP LRP-HSPG HSPG

Space of Disse

HEPATOCYTE

Reverse Cholesterol Transport – Role of HDLLCATCETP

• All cells can make Cholesterol

• Only HDL can pick up cholesterol from Peripheral Tissues

• Only the liver can degrade cholesterol

Liver

Pre-β-HDLABCA1

LCAT

apoA α -HDL

Hepatic lipase

SR-B1

apoA

VLDLREMNANT

VLDL/ CM Remnant

CELL

Phospholipids

Cholesterol

LCAT

Albumin

PLTP

CETP

HDL

Statins:HMG CoA ReductaseinhibitorsBile Acid

Seqestrants•Bind and remove bile in intestine•Increases cholesterol conversion to bile

Fibric Acids•Reduces synthesis of VLDL in liver•Increases catabolism of VLDL

Cholesterol Absorption Inhibitor Ezetimibe: •Inhibits transporter protein on surface of intestinal absorptive cells.•Blocks uptake of dietary cholesterol in small intestine.

Thank you

ABCA1 Transporter/ReceptorLarge plasma membrane spanning ATP dependent protein.

Essential for moving excess intracellular cholesterol and phospholipid to the plasma membrane.

Acts as a flipase, flipping cholesterol and phospholipid from inner leaflet of plasma membrane to outer leaflet.

Necessary for removing excess cholesterol from foam cells and preventing early steps in atherosclerosis.

ApoA-I is required for capturing the cholesterol released from the foam cell.

The Scavenger Receptor

(SR-A1 receptor)

How macrophages deal with oxidized or modified LDL

The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL.

Accumulation of these modified LDL in the cell leads to the accumulation of cholesterol droplets in the macrophage and the formation of foam cells.

Modification of LDL

LDL

Apo B-100

Derivatization:AldehydesGlucosylationeg. diabetes

Oxidation:Degradation of B-100 by reactiveoxygen species

Derivatized LDL

Oxidized LDL

LDL and AtherosclerosisFitting the pieces together

Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL

Artery wall

Monocyte

Endothelialcells

oxLDL

oxLDL (stimulates cytokine secretion)

Macrophage

Macrophage foam cell

Cytokines

Cytokines

Smooth muscle cellproliferation

HDL Protective RoleFitting the pieces together

oxLDL = oxidized LDLUC = unesterified cholesterol

ABCA1apoA-I

Endothelialcells

HDL

HDL

UC

PL

UC

Nascent HDL

HDL + UC

Macrophage foam cell

oxLDL

Monocyte

Arterywall

apo-B-48

apo-E

apo-C

apo-B-48

apo-E

apo-C

LCAT

Chylomicron remnant receptor

VLDL

LDL

LDL

SYNTHESIS OFCHOLESTEROL

SYNTHESIS OFLDL RECEPTORS

CHOLESTEROLESTERS

MEMBRANESSTEROIDSBILE ACIDS

HMG CoAReductase

ACAT

EXCESSCHOLESTEROL

LDLReceptors

DNA

RNA

INHIBITSINHIBITS

ACTIVATES

LDL DELIVERS CHOLESTEROL TO CELLS

Diameternm

Protein %

Triglycerides%

Cholesteryl esters %

Chylomicron 75-1200 1 88 3

VLDL 30-80 10 56 15

IDL 25-30 10 29 34

LDL 18-25 ~20 13 48

HDL 5-12 ~50 13 30

LDL-Receptors

Endosome Lysosome

Aminoacids

CholesterolLDL

Cholesteryl ester(storage)LDL

Receptors

HMG-CoAreductase

LDL

LDL Receptor (apoB-E receptor)

ACAT

Regulates cholesterol synthesis and plasma cholesterol levels