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