Lipoprotein Overview

Lipoprotein Particle Structure

Apolipoprotein

Apolipoprotein Apolipoprotein

NONPOLAR

LIPID CORE

Cholesterol Ester

Triglyceride

POLAR

SURFACE COAT

Phospholipid

Free cholesterol

Lipoprotein Subclasses

5 10 20 40 60 80 1000

Diameter (nm)

1.20

1.10

1.06

1.02

1.006

0.95

Den

sity

(g

/ml)

HDL2

HDL3

Chylomicron

Remnants

VLDL

IDL

Chylo-

microns

Lp(a)

LDL

Lipoprotein Classes

Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

HDLLDLChylomicrons,VLDL, and

their catabolic remnants

> 30 nm 20–22 nm 9–15 nm

D<1.006 g/ml D=1.019-1.063g/ml D=1.063-1.21 g/ml

Lipids Online

What do lipoproteins do?

Serve to transport lipid-soluble compounds

between tissues

Substrates for energy metabolism (TG)

Essential components for cells (PL, UC)

Precursors for hormones

Precursors for eicosanoids

Lipid soluble vitamins

Precursors for bile acids

The Players - Apolipoproteins

Apo AI (liver, small intestine)

Structural; activator of lecithin:cholesterol acyltransferase

(LCAT)

Apo AII (liver)

Structural; inhibitor of hepatic lipase; component of ligand for

HDL binding

Apo A-IV (small intestine)

Activator of LCAT; modulator of lipoprotein lipase (LPL)

Apo A-V (liver)

Direct functional role is unknown; regulates TG levels.

Apolipoproteins

Apo B-100 (liver)

Structural; synthesis of VLDL; ligand for LDL-

receptor

Apo B-48 (small intestine)

Structural; synthesis of chylomicrons; derived from

apo B-100 mRNA following specific mRNA editing

Apo E (liver, macrophages, brain)

Ligand for apoE receptor; mobilization of cellular

cholesterol

Apolipoproteins

Apo C-I (liver)

Activator of LCAT, inhibitor of hepatic TGRL

uptake

Apo C-II (liver)

Activator of LPL, inhibitor of hepatic TGRL uptake

Apo C-III (liver)

Inhibitor of LPL, inhibitor of hepatic TGRL uptake

Lipoprotein Metabolism

Exogenous/chylomicron pathway

(dietary fat)

Endogenous pathway (lipids

synthesized by the liver)

HDL metabolism (apolipoprotein

transfer, cholesteryl ester transfer,

reverse cholesterol transport

Lipoprotein Metabolism

Exogenous/chylomicron pathway

(dietary fat)

Endogenous pathway (lipids

synthesized by the liver)

HDL metabolism (apolipoprotein

transfer, cholesteryl ester transfer,

reverse cholesterol transport

Rutas Metabólica de las Lipoproteínas en Humanos

Lipoprotein Metabolism

Exogenous/chylomicron pathway

(dietary fat)

Endogenous pathway (lipids

synthesized by the liver)

HDL metabolism (apolipoprotein

transfer, cholesteryl ester transfer,

reverse cholesterol transport

Surface MonolayerPhospholipids (12%)Free Cholesterol (14%)Protein (4%)

Hydrophobic CoreTriglyceride (65%) Cholesteryl Esters (8%)

TG Rich: VLDL

Cholesterol and

Atherosclerosis, Grundy)

VLDL Biogenesis

Cholesterol and

Atherosclerosis, Grundy)

Microsomal

TG transfer

protein (MTP)Facilitates the

translocation, folding

of apoB and addition

of lipids to lipid

binding domains

TG and

cholesterol are

synthesized in

the liver as

VLDL which

contains apoB-

100

VLDL

Metabolism

Cholesterol and

Atherosclerosis, Grundy)

Apo C’s and apoE and

cholesteryl ester are

acquired from HDL in

circulation

Fatty Acid Transport

Cholesterol and

Atherosclerosis, Grundy)

ApoC-II activates

lipoprotein lipase which

catalyses the hydrolysis

of TG

VLDL

Metabolism

Cholesterol and

Atherosclerosis, Grundy)

Apolipoproteins are

transferred back to HDL

The end product is a

VLDL remnant (IDL)

Surface MonolayerPhospholipids (25%)Free Cholesterol (15%)Protein (22%)

Hydrophobic CoreTriglyceride (5%) Cholesteryl Esters (35%)

CE Rich: LDL

Cholesterol and

Atherosclerosis, Grundy)

LDL Metabolism

Cholesterol and

Atherosclerosis, Grundy)

Hepatic Lipase

Cholesteryl ester

transfer protein

LDL is removed by

apoB100 receptors

which are mainly

expressed in the

liver

LDL Cellular Metabolism

Cholesterol and

Atherosaclerosis, Grundy)

LDL are taken up by the LDL Receptor into clathrin-coated pits

LDL Cellular Metabolism

Cholesterol and

Atherosaclerosis, Grundy)

LDL dissociates from the receptor; the receptor recycles to the membrane

LDL Cellular Metabolism

Cholesterol and

Atherosaclerosis, Grundy)

In the lysosome, lipids are deseterified; proteins are hydrolyzed

LDL Cellular Metabolism

Cholesterol and

Atherosaclerosis, Grundy)

Increase in free cholesterol regulates decrease cholesterol synthesis

and uptake; increase cholesterol esterification

Lipoprotein Metabolism

Exogenous/chylomicron pathway

(dietary fat)

Endogenous pathway (lipids

synthesized by the liver)

HDL metabolism (apolipoprotein

transfer, cholesteryl ester transfer,

reverse cholesterol transport

Surface MonolayerPhospholipids (25%)Free Cholesterol (7%)Protein (45%)

Hydrophobic CoreTriglyceride (5%) Cholesteryl Esters (18%)

CE Rich: HDL

Cholesterol and

Atherosclerosis, Grundy)

HDL Subpopulations

Rye KA et al. Atherosclerosis 1999;145:227-238.

Apolipoprotein Composition

A-I HDL A-I/A-II HDL

A-II HDL

Particle Shape

Discoidal

Spherical

Lipid Composition

TG, CE, and PL

Particle Size

HDL2b HDL2a HDL3a HDL3b HDL3c

Lipids Online

HDL Maturation

Cholesterol and

Atherosclerosis, Grundy)

HDL is secreted in a

discoidal form from the liver

and gut.

As it acquires cholesterol

from tissues in the

circulation, it matures into a

spherical form through the

action of lecithin:cholesterol

acyl transferase

HDL MetabolismNascent HDL (lipid-poor apoA-I) is produced by the liver and intestine

Cholesterol Recycling

Cholesterol and

Atherosaclerosis, Grundy)