Lipoprotein

Structures, Function and Metabolism

(2)

Density Mobility Component

CM CM TG rich

VLDL Pre--lipoprotein TG rich

LDL lipoprotein Cholesterol rich

HDL lipoprotein Cholesterol/protein rich

Lipoproteins in plasma

Chylomicron

Transport dietary lipids from the intestine to the peripheral tissues

VLDL – IDL - LDL

• VLDL function: Deliver TG from liver to peripheral tissue cells

• LDL function: Deliver Cholesterol from live to peripheral tissue cells

Metabolism of VLDL and LDL

LDL• Cholesterol rich

• Can be taken up either by the peripheral tissues or by the liver

• LDL is taken up by LDL receptor through apoB100/LDL receptor interaction.

• After internazation, the LDL is digested by lysosomal enzymes. The cholesterol is released and the receptor recycles back to the membrane.

• LDL function: Deliver cholesterol from liver to peripheral tissue cells.

LDL receptor (839 aa)

extracellular domain isresponsible for apoB100/apoE binding

intracellular domain isresponsible for clustering of LDL receptors into clathrin- coated pit region of plasma membrane

LDL receptors exist in most peripheral tissues and in the liver.

Michael S. Brown and Joseph L. Goldstein discovered LDL-receptor.

1985 Nobel prize in Medicine

• LDL cholesterol levels are positively related to risk of cardiovascular disease

• Therefore, cholesterol in LDL has been called “bad cholesterol”

• Defects in the LDL receptor leads to familial hypercholesterolemia

Familial Hypercholesterolemia

• LDL-receptor deficiency – 420 different mutations identified – LDL-receptor activity: 0-25% of normal

• Classes of LDL-receptor mutations– 1 – no receptors– 2 – blockage of receptor from ER to Golgi Apparatus– 3 – receptor does not bind LDL normally– 4 – receptor does not accumulate in clathrin-coated pit– 5 – receptor fails to release LDL after internalization and does not

recycle to cell surface

Metabolism of HDL

HDL• HDL are synthesized in the liver and intestine as a small disc-like par

ticle.

• Proteins on the surface of HDL: apoAs, apoCs, apoE, CETP ， LCAT.

• Nascent HDL acquires cholesterol in peripheral tissues.

• The cholesterol is esterificated by LCAT (lecithin cholesterol acyltransferase) associated with the particle. This reaction is activated by apoA-I

• The cholesterol ester move to the hydrophobic core of the particle and particle becomes spherical.

HDL

• HDL particles bind to SRB1 receptors (scavenger receptor type B1) on the liver and are taken into the cells.

• HDL particles are also a reservoir for apolipoproteins (especially apoE & apoCII ）

• Some of the CE in HDL is transferred from HDL to other lipoproteins by cholesterol ester transfer protein （ CETP ）

HDL

• HDL salvage excess cholesterol from cells and reverse-transport cholesterol from peripheral cells to the liver for excretion

• HDL cholesterol levels are inversely related to risk of cardiovascular disease

• Therefore, cholesterol in HDL has been called “good cholesterol”

HDL

Main Functions of Lipoproteins

• CM: transfer exogenous lipids (dietary fat) from intestine to peripheral tissues.

• VLDL-LDL: transfer endogenous lipids from liver to peripheral tissues.

• HDL: reverse cholesterol transport from peripheral tissues to liver.

Lipoproteins (a) • Another kind of atherogenic lipoprotein.

• Consist of LDL and a protein designated as apo(a)

• The apo(a) is covalently linked to apoB-100 by a disulfide linkage

• High risk association with premature coronary artery disease and stroke.

Hyperlipoproteinemia

Fredrickson classification of hyperlipoproteinemia

Type IType I (hyperchylomironemia): Increased CM

Type II-A (hyper-Type II-A (hyper-lipoproteinemia)lipoproteinemia): Increased LDL Receptor deficiency or polygenic disorder.

Type II-BType II-B: Increased VLDL + LDL Increased production of VLDL and impaired LDL catabolism

Type IIIType III: (broad-lipoproteinemia)

Increased IDL, elevated cholesterol and triglycerides

Fredrickson classification

Type IVType IV: (hyper-pre--lipoproteinemia)

Increased VLDL

Impaired VLDL catabolism

Type VType V:

Increased CM + VLDL

Reduced lipoprotein lipase

Where do we get cholesterol?

• Our bodies make all the cholesterol we need.

• We also get cholesterol from foods we eat.

Blood cholesterol levels increase by eating these products

• Beef

• poultry,

• fish

• milk,

• eggs,

• cheese,

• yogurt, etc.

Why worry about cholesterol?• Blood cholesterol can stick to the sides of arteries.

• Blockages can form.

• It can lead to serious medical problems:

– Heart attack and

– Stroke.

What does my total cholesterol mean?

•200-239 mg/dL

HDL Cholesterol

LDL Cholesterol

Triglycerides