Lipid Transport

Question 1

How is lipid transported in the blood

Answer 1

Most is transported as lipoprotein particles

2% is carried bound non-covalently to albumin (mostly fatty acids released from lipolysis)

Question 2

What are lipoproteins made from

Answer 2

Variable amounts of different lipids - phospholipds, cholesterol, TAGs and cholesterol esters

Apoproteins

Question 3

What are the roles of aplipoproteins

Answer 3

Structural - involved in packaging non-water solube lipids into soluble form as multi-molecular particles

Functional - involved in activation of enzymes or in recognition of cell surface receptors

Question 4

Describe the structure of a lipoprotein

Answer 4

Spherical shape consiting of a surface coat and hydrophobic core

Surface coat - phospholipids, cholesterol, apoproteins (peripheral and integral)

Hydrophobic core - TAGs and cholesterol esters

Lipoproteins are only stable if they maintain their spherical shape which is dependent on the ratio of core to surface lipids, so as core is reduced, surface coat must be reduced

Question 5

Name some peripheral apolipoproteins

Answer 5

apoC and apoE

Question 6

Name some integral apolipoproteins

Answer 6

apoA and apoB

Question 7

Which are the two importmant apolipoproteins and on which lipoproteins are they found

Answer 7

apoB - VLDL, IDL, LDL

apoAI - HDL

Question 8

What are the classes of lipoproteins and what do they do

Answer 8

Chylomicrons - transport dietary TAG from intestint to tissues

VLDL - transport TAG from liver to tissue

IDL - short-lived precursor for LDL, transport cholesterol from liver to tissue

LDL - transport cholesterol from liver to tissue

HDL - tranport excess cholesterol from tissue to liver

Question 9

What enzymes are involved in lipoprotein metabolism

Answer 9

Lipoprotein lipase

Lecithin Cholesterol Acyltransferase (LCAT)

Question 10

What is lipoprotein lipase

Answer 10

Enzyme found on inner surface of capillaries in muscle and adipose tissue that removes core TAG from lipoprotein particles like chylomicrons and VLDLs

Insulin increases synthesis of the enzyme

It hydrolyses TAG into fatty acids and glycerol, fatty acids taken up by tissues, glycerol taken to liver

Requires ApoC-II as cofactor

Question 11

What is LCAT

Answer 11

Enzyme that both forms lipoprotein particles and maintains their structure by converting some surface lipid to core lipid

It converts cholesterol to cholesterol ester using fatty acid derived from lecithin

Question 12

Describe how dietary TAG reaches tissues

Answer 12

TAG hydrolysed in small instestine using pancreatic lipase

Fatty acids enter epithelial cells of small intestine where they are re-esterified back to TAGs

TAGs are packaged with other dietary lipids into chylomicrons with apoB-48 added to the surface

Chylomicrons released into lymphatics

They enter bloodstream as thoracic duct which empties into left subclavian veins where the chylomicron aquires apoC and apoE

Chylomicron is carried to tissue where apoC binds to lipoprotein lipase and TAG is hydrolysed and fatty acids released

Question 13

Describe how chylomicron ends up at the liver

Answer 13

When TAG reduced to 20% in chylomicron, apoC dissociates and chylomicron forms a chylomicron remnant

Remnant returns to liver where LDL receptor binds apoE and remnant taken up by receptor mediated endocytosis

Question 14

Describe how a VLDL particle gets from the liver to the tissue

Answer 14

VLDL made in the liver with apoB100 added during formation and apoC and apoE being added later from HDL in the blood

VLDL binds to LPL on capillary endothelial cells and starts to become depleted of TAG

As TAG content of VLDL drops, some VLDLs dissociate from LPL and return to the liver

Question 15

Describe how a VLDL becomes an LDL

Answer 15

If VLDL depletes to 30%, the particle becomes an IDL particle

IDL can be taken up by liver or rebind to LPL to further deplete TAG content

Upon depletion to 10%, IDL loses apoC and apoE to become an LDL particle (with high cholesterol content)

Question 16

How do cells obtain cholesterol from LDL particles

Answer 16

Receptor-mediated endocytosis

In this process, LDL particles are taken up by the cell and the cholesterol is released inside the cell

LDL receptors are expressed by cells requiring cholesterol

LDL receptors recognise and bind apoB100, then this complex is taken in by endocytosis and subjected to lysosomal digestion

Cholesterol esters are converted to free cholesterol during this process

This process inhibits synthesis of cholesterol by the cell and reduces synthesis and exposure of LDL receptors

Question 17

How do LDL particles cause harm to the body

Answer 17

LDL particles have a long half-life so are susceptible to oxidative damage which leads to them being recognised and engulfed by macrophages

Macrophages become foam cells and accumulate in intima of blood vessel wall forming fatty streak

Fatty streak evloves into atherosclerotic plaque which grows and encroaches on lumen - may lead to angina

Plaque may rupture triggering acute thrombosis which may lead to stroke or MI

Question 18

What inherited condition involves the LDL receptor

Answer 18

Familial hypercholesterolaemia

Question 19

What is familial hypercholesterolaemia

Answer 19

Where there is an absence or deficiency of functional LDL receptors

So there is elevated levels of LDL and cholesterol in the plasma

Question 20

What is the function of HDL particles

Answer 20

Transport excess cholesterol from tissues to the liver for disposal and to other cells requiring additional cholesterol

Question 21

How are HDL particles formed and how do they work

Answer 21

Synthesised by liver and intestine but some bud off from chylomicrons and VLDLs as they are digested

HDL fills with phospholipid and cholesterol and returns to liver to dispose cholesterol as bile salts

ABCA1 protein within cells facilitates transfer of cholesterol to HDL by reverse cholesterol transport

Cholesterol then converted to cholesterol ester by LCAT

Question 22

How can cells requiring cholesterol obtain it from HDL particles

Answer 22

They utilise a scavenger receptor - SR-B1

Question 23

What is used to transfer cholesterol ester and TAG between HDL and VLDL particles

Answer 23

Cholesterol exchange transfer protein

Question 24

What are dyslipoproteinaemias

Answer 24

Any defect in the metabolism of the plasma lipoproteins, either primary or secondary

Question 25

What are the clinical symptoms of hyperlipoproteinaemias

Answer 25

High cholesterol in blood

Cholesterol deposits in skin:

• Xanthelasma
• Tendon xanthoma
• Corneal arcus

Question 26

What are the three types of hyperlipoproteinaemias and what causes them

Answer 26

Type I - chylomicrons in fasting plasma, no link with coronary artery disease, caused by defective LPL

Type IIa - associated with coronary artery disease that may be severe, caused by defective LDL receptor

Type III - raised IDL and chylomircon remnants, associated with coronary artery disease, caused by defective apoE

Question 27

What is the treatment of hyperlipoproteinaemia

Answer 27

Diet and lifestyle modifications

Statins - reduce cholesterol synthesis in liver (inhibits HMG-CoA reductase), also increases expression of lipoprotein lipase

Bile salt sequestrants (cholestyramine) - lowers cholesterol by increasing disposal from the body