L4: Lipid Transport

Question 1

State 5 main classes of lipids (and any subdivision of each)

Answer 1

Question 2

What is a phospholipid with a head group:

• Choline
• Inositol

… named?

Answer 2

• Choline = phosphatidylcholine
• Inositol= phosphatidylinositol

Question 3

Why must lipids be transported in blood bound to a carrier? State the two most common trrasnporters.

Answer 3

Lipids are hydrophobic hence in soluble in water (so insolube in blood).

• 98% carried by lipoprotein particles
• 2% carried by albumin

Question 4

How does our body obtain cholesterol? (2 ways)

Answer 4

• Most of our cholesterol synthesised by liver
• Some obtained from diet

Question 5

How is cholesterol transported around the body?

Answer 5

As a cholesterol ester in the core/cargo & in the phospholipdid monolayer of a lipoprotein.

Question 6

State three uses of cholesterol in body

Answer 6

• Precursor for bile salts
• Precursor for steroid hormones
• Phospholipid membranes (modulates fluidity)

Question 7

Describe how cholesterol is converted into a cholesterol ester, include:

• starting products
• end products
• enzymes

Answer 7

Question 8

(Most likely will be given this in exam but…) Estimate teh typical plasma ranges of:

• Total cholesterol
• Total lipids

… in plasma

Answer 8

Question 9

Describe the structure of a lipoprotein, including:

• Cargo
• Surrounding monolayer
• Peripheral & interal proteins

Answer 9

Lipids are in NON-COVALENT association with apoproteins. They contain variable amounts of lipids.

Question 10

State 3 generic roles of lipoproteins

Answer 10

• Transport lipids in blood
• Activate enzymes (e.g. lipoprotein lipase)
• Recognition of cell surface receptors

Question 11

State the 5 lipoproteins

Answer 11

Fat carriers:

• Chylomicrons
• VLDL

Cholesterol ester carriers:

• IDL
• LDL
• HDL

Each contains a variable content of apolipoprotein, TAG, cholesterol & cholesterol ester

Question 12

Describe and explain the stability of lipoproteins

Answer 12

Lipoproteins only stable if they maintain spherical shape; spherical shape is dependent on ratio of core: surface lipids. Hence, as lipids are removed from the core (by lipases or transfer proteins) lipids from surface coat must also be removed.

Question 13

Describe the relationship between diameter and density of lipoproteins

Answer 13

Diamter is inversely proportional to density

Question 14

Describe the function of each of the 5 lipoproteins (chylomicrons, VLDL, IDL, LDL & HDL)

Answer 14

Question 15

State the 6 main classes of lipoprotein and which is most important for:

• VLDL, IDL, LDL
• HDL

Answer 15

Major classes: A, B, C, D, E & H

• VLDL, IDL, LDL: apoB
• HDl: apoAI

Question 16

State two roles of apolipoproteins (structural & functional)

Answer 16

• Structural: packaging water insoluble lipids
• Functional: cofactors for enzymes & ligands for cell surface receptors

Question 17

Describe how/why apolipoproteins are able to carry hydrophobic lipids in blood

Answer 17

Lipoproteins have phospholipid monolayer with hydrophobic tails pointing inwards (towards where main cargo lipids are carried) and hydrophilic heads pointing outwards into blood. Apoproteins also have hydrohobic and hydrophilic parts which enables them to interact with both lipids and water.

Question 18

Describe chylomicron metabolism

Answer 18

• Pancreatic lipase hydrolyses TAGs into glycerol & fatty acids (because TAGs cannot be absorbed directly)
• Fatty acids enter epithelial cells of small intestine
• Fatty acids are then re-esterified back to TAGs using glycerols phosphate (produced from glucose metabolism)
• Packaged with other lipids (e.g. cholesterol, fat soluble vitamins) into chylomicrons. ApoB-48 is added
• Enter lymphati system, via lacteals, travelling through thoracic ducts into left sublclavian vein
• In blood, acquires apoC & apoE
• apoC binds to lipoprotein lipase on endothelial cells of capillaries in muscle & adipose tissue causing release of FA into cells
• TAG content reduced to ~20%, apoC dissociates forming chylomicron renmant
• Chylomicron returns to liver where apoE binds to LDL receptor on hepatoytes & chylomicron remnant is taken up by receptor mediated endocytosis
• Lysosomes release remaining contents for use in metabolism

Question 19

For lipoprotein lipase, state:

• Role
• Cofactor required
• Where found

Answer 19

• Role: hydrolyses TAGs in lipoproteins
• Requires ApoC-II as a cofactor
• Found attached to surface of endothelial cells in capillaries

Question 20

Describe VLDL metabolism

Answer 20

1. VLDL made in liver (for transporting TAGs synthesised in liver to other tissue e.g. adipose tissue for storage)
2. ApoB100 is added during synthesis in liver
3. When VLDL enters blood, apoC & apoE are added from HDL particles
4. VLDL binds to lipoprotein lipase (on surface of endothelial cells in muscle & adipose tissue) and starts to become depleted of TAGs

• In muscle, released fatty acids are taken up & used for energy production
• In adipose, released fatty acisd are used for re-synthesis of TAGs and stored as fat

5. As TAG content in VLDL depletes, some VLDLs dissociated from LPL and return to liver. However, if VLDL remains bound and TAG content depletes to ~30% it becomes a short lived IDL particle

Question 21

Describe IDL & LDL metabolism

Answer 21

IDL (made from VLDLs which have been depleted of TAGs to ~30%)

1. Taken up by liver OR rebind to lipoprotein lipase to further deplete TAG content
2. If TAG depletes to ~10% then apoC & apoE are lost and IDL becomes an LDL (with high cholesterol content)
3. LDL can be taken up by peripheral tissues (which express LDL receptor) OR cleared by the liver (but this is inefficient as liver LDL receptor has high affinity for apoE which LDLs don’t have)
4. If LDL taken up by cells, lysosomes will digest LDLs to release fatty acids & cholesterol

HOWEVER, whilst in blood, LDLs susceptible to oxidative damage and may be taken up by macrophages to form foam cells which accumulate to form a fatty streak leading to atherosclerosis.

Question 22

Cells that require cholesterol will express what receptor? The expression of this receptor is controlled by what?

Answer 22

Cells will express LDL receptor on surface so that it can bind LDLs and then use its lysosomes to break LDLs down into fatty acids & cholesterol.

LDL receptor expression is controlled by [cholesterol] in cell e.g. if high [cholesterol] then fewer LDL receptors will be expressed

Question 23

Why are LDLs more susceptible to oxidative damage than other lipoproteins?

Answer 23

LDLs have a longer half life in the blood hence are more susceptible to oxidative damage

Question 24

State three ways in which nascent (immature) HDL particles can be synthesised

**Immature HDL particles have low TAG content

Answer 24

• Synthesised by liver & small intestine
• Bud off from chylomicrons & VLDLs as they are digested by lipoprotein lipase
  *

Question 25

Describe how LDLs are taken up by cells that require cholesterol, include: - Ligand - Mechanism by which taken up - Fate once taken up

Answer 25

Receptor mediated endocytosis Apo-B100 binds to LDL recptor on surface of cell that requires cholesterol. LDL-receptor complex taken in by cell via endocytosis. Endosome then fuses with lysosome so that LDL can be broken down into fatty acids & cholesterol esters (which can be converted into cholesterol)

Question 26

Describe HDL metabolism/how they transport excess cholesterol from cells to liver

Answer 26

1. Nascent HDLs accumulate phospholipids & cholesterol from endothelial cells of blood vessels via **reverse cholesterol transport which is facilitated by the ABCA1 protein.** *NOTE: traansfer of phospholipids doesn't require protein or enzyme* 2. Cholesterol is then converted into cholester esters by **LCAT (lecithin cholesterol actyltransferase).** Hollow core of HDL is now progressively filling with phospholipids & cholesterol 3. HDLs then have 3 possible fates: * Taken up by liver via receptor mediated endocytosis * Cells that require additional cholesterol can use scavenger receptor to take cholesterol from HDL via receptor mediated endocytosis * HDL can exchnage cholesterol ester for TAG with VLDL using **CEPT (cholesterol exchnage transfer protein)**

Question 27

Define dyslipoproteinaemia

Answer 27

Defect in metabolism of lipoproteins Can be primary (e.g. genetic) or secodnary (e.g. acquired due to diet, drugs or disease such as diabetes)

Question 28

Define hyperlipoproteinaemia and state two possible causes

Answer 28

Raised plasma [lipoproteins] which may be due to: * Under removal due to defects in enzymes, receptors or apoproteins * Overproduction

Question 29

Describe 4 signs of hypercholesterolaemia

Answer 29

* High plasma [cholesterol] * Xanthelasma (yellow patches on eyelids) * Tendon xanthoma (nodules on tendon) * Corneal arcus (white circle around eye. Common in elderly) All due to deposition of cholesterol

Question 30

Explain how hyperlipoproteinaemias are treated

Answer 30

**First approach:** * Diet: reduce cholesterol & saturated fat, increase fivre * Lifestyle: increase exercise, quit smoking **If no response... drugs:** * Statins: reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin * Bile salt sequestrants: bind bile salts in the GI tract causing the liver to produce ore bile acids and hence use more cholesterol e.g. colestipol

Question 31

Describe how/why raised serum LDL is associated with atherosclerosis

Answer 31

Question 32

Describe statins mechanism of action

Answer 32

\*\*Secodnary effect of statins is to increase expression of lipoprotein lipase

Question 33

Fredrickson system (also known as WHO system) is used to identify and classify hyperlipoproteinaemias; state & describet the 6 classes

Answer 33

NOTE: type IIa is known as familial hypercholesterolaemia; it can be homozygous (absence of functional LDL receptors) or heterozygous (deficiency of functional LDL receptors)

Question 34

For each of the receptors or enzymes, state with apoprotein it binds: - Lipoprotein lipase - LDL receptor

Answer 34

* Lipoprotein lipase= apoC (specificaly apoC-II) * LDL receptor= apoB100 & apoE