lipoprotein 2

Lecture 4 – March 18, 2010

LIPIDS: LIPOPROTEINS/TRANSPORT

General Features of Lipoproteins

Apolipoproteins: specific lipid-binding proteins that attach to the surface intracellular recognition for exocytosis of the nascent particle after

synthesisactivation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance.

Main lipid components: triacylglycerols, cholesterol esters, phospholipids. Major lipoproteins:

chylomicronsvery low density lipoproteins (VLDL)low density lipoproteins (LDL) high density lipoproteins (HDL)

Subfraction: intermediate density lipoproteins (IDL)

Electrophoretic mobility (charge):HDLs = lipoproteinsLDLs = -lipoproteins VLDLs = pre- lipoproteins (intermediate between and mobility).

Figure 1. Model of low density lipoprotein. Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule

0%

20%

40%

60%

80%

100%

Chylo-microns

VLDL LDL HDL

Lipoprotein Type

Composition

C

P

T

C

P

T

T

P

C

C P

T

Figure 2. The major classes of lipoproteins and their relative content of triacylglycerol (T), cholesterol (C) and protein (P).

LIVER

ApoB48 aids with chylo-micron assembly

Lymph system:Chylomicrons to capillaries via lymph

I N T E S T I N E

non-hepatic tissuesnon-hepatic tissues

C E C EC EC E C E

C EC E C E

C E

Figure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues

and the remnants take cholesterol to the liver

Nascent chylo-microns acquire apo CII (C) and E (E) from HDL

chylomicron interacts with lipoprotein lipase removing FFA

Chylomicron (or VLDL)

Apo CIILIPOPROTEIN LIPASE

PolysaccharideChain

EndothelialSurface of cell

Triacylglycerolin core

Free fatty acids

Glycerol

To Liver

Free fatty acidsIn cellulo (muscle & adipose)

Capillary

Figure 4. Lipoprotein lipase action on chylomicron triacylglycerol (an identical reaction occurs with VLDL)

LIVER

ApoB48chylomicron remnants lose CII to HDL


C E C E

E

E

E

EC

C

C

C EC E C E

C E

EE E

Liver: apo E receptor takes up remnants to deliver cholesterol

Figure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver

Lymph system:

I N T E S T I N E

C E C EC E

chylomicron acquires apo CII (C) and E (E) from HDL

chylomicron interacts with lipoprotein lipase removing FFA

B100 (B) helps assemble and export nascent VLDL

LIVER

nascent VLDL acquires apo CII (C) and apo E (E) from HDL

C EC E C E C EC E C EC E

C EC E

B B

B

BB

B BB

bile acids

HDL scavenge cholesterol

C EC E

B BB

Figure 5. The liver-directed endogenous pathway of lipoprotein metabolism.


LPL hydrolyze TAGs; FFA uptake; LDL circulate to tissues

apo B100 on LDL bind to receptor

LDL taken into the cell to deliver cholesterol

CII and E release to HDL

Apo E binds liver receptor

Cholesterol uptake; excreted as bile acids

Nascent Chylomicron Assembly in Gut Mediated by B48

Nascent HDL Assembled in liver Loans apo E/ apo CII

to nascent chylomicrons

Mature Chylomicron Apo E and CII

added from HDL

Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle

Mature HDL CE from peripheral cells via

LCAT activated by apo A1 Apo CII returned by

chylomicrons

Chylomicron Remnant from mature chylomicron apo CII returned to HDL

Chylomicrons: Exogenous Pathway

HDL: Both Pathways

apo CII

Triacylglycerol Cholesterol ester

Phospholipid

E

CII A1

E B48 CII

A1

E

CII

B48

apo E & CII from HDL

B48

adipose &muscleFFA

CII

CII

CII

CII

E

EE

E

CII

CII

Fig. 6 Chylomicron Processing and Interface with HDL

Mature Chylomicron Apo E and CII

added from HDL CII activates LPL

B48

Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle

LDL from mature VLDL

A1

CII

B100

Nascent VLDL Assembly in Liver Mediated by B100

VLDL/LDL: Endogenous Pathway

HDL: Both Pathways

E

CIIA1

Fig. 6 VLDL/LDL Processing and Interface with HDL

Mature VLDL Apo E and CII

added from HDLE

CII

B100

apo CII & E from HDL

EE

E

E

CII

CII

CII

adipose &muscle FFA

apo CII + EE

CII

EEE

CII

CII

Mature HDLApo CII/E returned by VLDL

B100

B100

Mature VLDL Apo E and CII

added from HDL CII activates LPL

E Receptor

Mature HDL

CE Metabolism Bile acids

Chylomicron Remnant

E Receptor

B100receptor

LDL

Fig. 6 Clearance of Cholesterol by Liver from Chylomicron Remnants, HDL and LDL

E

B48

E

B48

E

B48

A1

EA1

E

A1

E

B100

B100

B100

Pathogenesis

Oxidized LDL

1. Uptake by "scavenger receptors" on macrophages that invade artery walls; become foam cells2. Elicits CE deposition in artery walls3. Atherosclerosis/CAD can develop

Figure 6. Consequence of Oxidized LDL Formation

Oxidation of LDL

LDL

free pool ofcholesterol

LDLCE

endocytosis

late endosome

ACEHCE cholesterolB100 amino acids

NPC-1 mediated transfer

Cholesterol Esterase

Cholesterol metabolism to bile acids or steroids

Golgi

Cholesterol release for transport to liver

MembraneCholesterol

ACAT (stimulated by cholesterol)

CE CE

CE stored in droplets

CERPL C A T

Apo A1 receptor

A1

CII

EA1

ECIICE in nascent HDL

Apo A1 binds to receptor, activates CERP to pump out cholesterol, and LCAT to esterify cholesterol

Mature HDL:Cleared by liver

ooo

clathrin-coated pit

LDL receptor

ooo

vesicle

Recycling of receptor

transport vesicle- lysosome fuse forming late endosome

sorting endosome: ligand/receptor dissociation

lysosome

Figure 7. Cellular cholesterol uptake, metabolism and release.

ReverseCholesterolTransport

Recycling of receptor and clathrin

Lipoprotein classes:

Lipo-protein

Source Apo Proteins in

Mature

Protein:Lipid/Major (minor) Lipid

Transported

Function

Chylo-microns

gut B48, CII*, E*

1:49triacylglycerol (CE)

Dietary:FFA Adipose/muscleCE Liver via remnants

VLDL liver B100, CII*, E*

1:9triacylglycerol (CE)

Synthesized:FFA adipose/muscleCE LDL

LDL blood B100 1:3cholesterol ester

CE to liver (70%) and peripheral cells (30%)

HDL liver A1, CII, E("ACE")

1:1cholesterol ester

supplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport

Functions of Apolipoproteins & Enzymes in Lipid Transport/Processing

Protein (Enzyme)

Site of Action Activator Function

LPL (Enzyme) capillary walls apo CIIexcises FFA from TAGs in chylomicrons and VLDLs for adipose and muscle

ACAT (Enzyme) inside cells free choles cholesterol ester storage

LCAT (Enzyme) blood apo A1cholesterol extraction from cells HDL carries CE for liver clearance (to bile acids)

CERPplasma

membrane

apo A1 (choles.Induced)

flips cholesterol (and lecithin) to outer layer of lipid bilayer for LCAT action in blood

TTPintestine/liver

smooth ERnone loads TAGs onto B48 (gut) and B100 (liver)

Apo A1blood, plasma

membranenone

activates LCAT and CERP; binds to apo A1 receptors on cells requiring cholesterol extraction

Apo B48 Gut none export of chylomicrons from intestinal cells

Apo B100 Various cells none ligand for LDL receptor; export of liver VLDL

Apo CII capillary walls none activates lipoprotein lipase

Apo E liver none receptor ligand - clears remnants, IDL, and HDL

lipoprotein 2

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