Lipoproteins

Chylomicrons (CM)

Triacylglycerols associate with specific proteins and a small amount of phospholipid and cholesterol to form these lipoprotein transport particles:

• These particles are composed of 98% triacylglycerols with the proteins and phospholipid on the surface

• They are released into the lymph system and then into the blood

Spherical Particles

Carry lipids through plasma:

• The surface is made of protein (called apolipoprotein) and a phospholipid monolayer

• The interior contains cholesterol, triacylglycerols, and cholesteryl esters

Lipoprotein Particles

Cholesterol and TAGs are packaged into these particles for transport through bodily fluids:

• Each particle consists of a core of hydrophobic lipids surrounded by a shell of more-polar lipids and proteins

• Can shift between classes as they release or pick up cargo, thereby changing their density

The protein components of lipoprotein particles (called apolipoproteins) have two roles:

1. They solubilize hydrophobic lipids.

2. They contain cell-targeting signals.

Order of Lipoproteins According to Increasing Density

1. chylomicrons

2. chylomicron remnants

3. very low-density lipoproteins (VLDLs)

4. intermediate-density lipoproteins (IDLs)

5. low-density lipoproteins (LDLs)

6. high-density lipoproteins (HDLs)

TAGs and cholesterol in excess of the liver’s own needs:

are exported into the blood in the form of very low-density lipoprotein (VLDL).

TAGs in VLDL

hydrolyzed by lipoprotein lipase

Intermediate-Density Lipoproteins (IDLs)

• The cholesterol-rich remnants after fatty acids are taken into the cells

• They are rapidly converted into low-density lipoprotein (LDL) by the removal of more TAGs

Low-Density Lipoprotein

• The major carrier of cholesterol in blood

• This lipoprotein particle contains a core of cholesterol molecules linked by ester bonds to fatty acids (cholesterol ester).

Structure of LDL

• The core is surrounded by a shell of phospholipids and unesterified cholesterol

• The shell also has a single copy of apoprotein B-100, which directs LDL to the proper cells.

The Role of LDL

To transport cholesterol to peripheral tissues and regulate de novo cholesterol synthesis at these sites

High-Density Lipoprotein (HDL)

They pick up cholesterol from extra-hepatic tissues and bring it back to the liver in a process termed reverse cholesterol transport.

Chylomicrons

• Diet derived, packaged in the intestine to deliver lipids to various tissues

• ApoB-48 is associated

• ApoC-II activates lipoprotein lipase to release free fatty acids for fuel in adipose tissue, heart, and skeletal muscle.

• Remnants go to the liver for absorption via apoE-mediated endocytosis

VLDL

• Packaged in the liver from diet derived and de-novo synthesized lipids

• ApoB-100 is associated

• ApoC-II activates lipoprotein lipase to release free fatty acids.

• Adipocytes take up free fatty acids, and convert them to TAGs for storage.

• Muscle uses the TAG for energy.

LDL

• Delivers cholesterol to various tissues.

• For example, muscle and adipose tissue have LDL-receptors and recognize apoB-100 on LDL.

HDL

• Picks up cholesterol from extra-hepatic tissues and returns to liver (reverse-cholesterol transport), where it can be metabolized.

• Apolipoprotein-A is associated

Cholesterol metabolism must be precisely regulated:

to prevent atherosclerosis, the thickening of arterial walls with a subsequent loss of elasticity

The primary source of cholesterol for peripheral tissues:

the LDL

High concentrations of LDL in the blood:

play a role in setting the conditions for a heart attack

Receptor-Mediated Endocytosis

• normally removes LDL in the blood

• serves as a paradigm for the uptake of many molecules

Steps of Receptor-Mediated Endocytosis of LDL

1. LDL binds to a receptor protein on the cell surface:

• Apoprotein B-100 on the surface of an LDL particle binds to a specific receptor protein (LDL-receptor) on the plasma membrane of nonliver cells.

2. The cell internalizes the receptor–LDL complex:

• The plasma membrane in the vicinity of the complex folds in on itself (invaginates).

• The membrane then fuses to form an endocytic vesicle (called an endosome), enclosing the receptor–LDL complex (endocytosis).

3. LDL is hydrolyzed in lysosomes:

• The vesicles containing LDL subsequently fuse with lysosomes, acidic vesicles that carry a wide array of degradative enzymes.

• The protein component of the LDL is hydrolyzed to free amino acids.

• The cholesteryl esters in the LDL are hydrolyzed by a lysosomal acid lipase.

• The LDL receptor itself usually returns to the plasma membrane.

• The round-trip time for a receptor is about 10 minutes; in its lifetime of about a day, it brings many LDL particles into the cell.

The vesicles containing LDL subsequently fuse with lysosomes, acidic vesicles that carry a wide array of:

degradative enzymes

The protein component of the LDL:

is hydrolyzed to free amino acids

The cholesteryl esters in the LDL:

are hydrolyzed by a lysosomal acid lipase

The released unesterified cholesterol can then be used for:

membrane biosynthesis or re-esterified for storage inside the cell

The stored cholesterol:

must be re-esterified because high concentrations of unesterified cholesterol disrupt the integrity of cell membranes

When cholesterol is abundant inside the cell:

new LDL receptors are not synthesized, blocking the uptake of additional cholesterol from plasma LDL

Niemann–Pick Diseases

• They are a group of lipid storage disorders of varying severity

• One fatal variety is caused by the accumulation of cholesterol in lysosomes that results in multiple organ failure

High Cholesterol Levels

Promote atherosclerosis, which is the leading cause of death in industrialized societies

Familial Hypercholesterolemia

is characterized by high concentrations of cholesterol and LDL in the plasma, about three to four times the desired amount

• cholesterol is deposited in various tissues because of the high concentration of LDL cholesterol in the plasma

• the cholesterol is not degraded, so its improper transport and disposal results in unwanted accumulation

Excess LDL

forms oxidized LDL (oxLDL), which can stimulate the inflammatory response by the immune system—initiating the process of plaque formation

oxLDL

taken up by immune-system cells called macrophages

Macrophages

become engorged to form foam cells

Foam Cells

• become trapped in the walls of the blood vessels

• contribute to the formation of atherosclerotic plaques that cause arterial narrowing and lead to heart attacks

Homozygotes

• have almost no functional receptors for LDL

• most die of coronary artery disease in childhood

Heterozygote

• have about half the normal number

• (1 in 500 people) has a milder and more variable clinical course

HDL has a number of antiatherogenic properties:

• the inhibition of LDL oxidation

• the removal of cholesterol from cells, especially macrophages

• retrieves cholesterol from other tissues in the body to return the cholesterol to the liver for excretion as bile or in the feces

When reverse cholesterol transport fails:

macrophages become foam cells and facilitate the formation of plaques

Bile Salts

are cholesterol derivatives that promote the absorption of dietary cholesterol and dietary fats

• de novo synthesis of cholesterol is blocked