Lipid Transport

Question 1

Lipids are insoluble, Why is this a problem?

Answer 1

The fact that lipids are hydrophobic is a problem for transport in blood. They are instead transported in blood bound carriers.

Question 2

What is a cholesterol ester?

Answer 2

A cholesterol with a fatty acid added to it.

Question 3

How are lipids transported in the blood?

Answer 3

The are bound to blood bound carriers.

2% of lipids (mostly fatty acids) are carried bound to albumin BUT, this has limited capacity (3mmol).

98% of lipids are carried to lipoprotein particles consisting of phospholipid, cholestrol, cholestrol esters, proteins and TAG.

Question 4

What should total Cholestrol in blood be?

Answer 4

Total cholestrol should be under 5 mmol/L

Question 5

What is the most common head group of phospholipids?

Answer 5

Choline to make phosphatidylcholine.

Inositol is another head - forms phosphatidylinositol.

Question 6

What different shaped structures can phospholipids form?

Answer 6

• Bilayer sheet
• Liposome
• Micelle

Question 7

Where is most cholesterol synthesised?

Answer 7

Some cholestrol is obtained from the diet but most is synthesised in the liver.

Question 8

Why is cholestrol essential?

Answer 8

• Cholestrol is an essential component of membranes (modulates fluidity).
• Precursor of steroid hormones
  
  • Cortisol
  • Aldosterone
  • Testosterone
  • Oestrogen.
• Precursor of bile acids.

Question 9

How is cholestrol transport?

Answer 9

It is transported around the body as cholestrol esters.

The enzymes lecithin cholestrol acyltransferase (LCAT) or acyl-coenzyme A cholestrol acyltransferase esterify the cholestrol with a fatty acid.

Question 10

What is the structure of a lipoprotein?

Answer 10

• Peripheral Apolipoproteins (apoC, apoE)
• Integral Apolipoproteins (apoA, apoB)
• Phospholipids monolayer with small amount of cholestrol
• Cargo consisting of:
  
  • Triacylglycerol
  • Cholestrol esters
  • Fat soluble vitamins

Question 11

What are the five classes of lipoproteins?

Answer 11

Chylomicrons - Fat

VLDL (very low density lipoproteins)

IDL (intermediate density lipoproteins)

LDL (low density lipoproteins) -bad cholesterol

HDL (high density lipoproteins) - good cholesterol

Each contains a variable content of apolipoprotein, triglyceride, cholestrol and cholestrol esters.

Question 12

How big are each of the lipoproteins?

Answer 12

Question 13

How do you obtain the density of lipoproteins? What is density inversely proportional to?

Answer 13

Density obtained by flotation ultracentrifugation.

Particle diameter is inversely proportional to density

Question 14

What are Apolipoproteins?

Answer 14

Each class of lipoprotein particle has a particular complement of associated proteins (Apolipoproteins).

There are 6 major classes of apolipoprotein (A,B,C,D,E,H).

They can be integral (passing though the phospholipid bilayer) or peripheral (resting on top)

Question 15

What are the most important apolipoproteins?

Answer 15

apoB (VLDL, IDL, LDL) and apoA1 (HDL)

Question 16

What are the two roles of apolipoproteins?

Answer 16

Structural: Packaging a water insoluble lipid.

Functional: co-factor for enzymes and ligand for cell surface receptors.

Question 17

How are chylomicrons metabolised?

Answer 17

Chylomicrons are loaded in small intestine and apoB-48 added before entering the lymphatic system.

Travel to thoracic duct which empties into left subclavian vein and acquire 2 new apoproteins (apoC and apoE) once in blood.

apoC binds to lipoprotein lipase (LPL) on adipocytes and muscle. Releasing fatty acids enter cells depleting chylomicrons of its fat content.

When triglyceride reduce to about 20% apoC dissociates and chylomicrons become a chylomicrons remanant.

Chylomicron reminants return to the liver, LDL receptors on hepatocytes bind apoE and chylomicron remnant taken up by receptor mediated endocytosis. Lysosomes release remaining contents for use in metabolism.

Question 18

What is lipoprotein lipase?

Answer 18

Lipoprotein lipase is an enzyme on the capillary walls of muscle and adipose. It hydrolyses triacylglycerol in lipoproteins and requires apoC-II as a cofactor.

Question 19

How are VLDLs metabolised?

Answer 19

VLDL are made in the liver fo the purpose of transporting triacylglycerol (TAG) to other tissues.

Apolipoproteins apoB-100 added during formation and apoC and apoE added from HDL particles in blood.

VLDL binds to lipoprotein lipase (LPL) on endothelial cells in muscle and adipose and starts to become depleted of triacylglycerol.

In muscle the released fatty acids are taken up and used for energy production.

In adipose the fatty acids are used for re-synthesis of triacylglycerol and stored as fat.

Question 20

How are IDL and LDL metabolised?

Answer 20

VLDL becomes IDL which becomes LDL.

As the triacylglycerol content of VLDL particles drop, they dissosiate from the LPL enzyme complex and return to the liver.

If VLDL content depletes to 30%, the particle brcomes a short lives IDL particle.

IDL particles can also be taken up by the liver or rebind to LPL enzymes to further deplete in TAG content.

Upon depletion to 10%, IDL loses apoC and apoE and becomes an LDL particle (high cholestrol content).

Question 21

Why are LDL bad?

Answer 21

Because they promote cardiovascular disease.

Question 22

What are the functions of LDL?

Answer 22

The primary function of LDL is to provide cholestrol from liver to peripheral tissues

Peripheral cells express LDL receptor and take up LDL via process od receptor mediated endocytosis.

Importantly LDL do not have apoC or apoE so are not efficiently cleared by liver (LIver-LDL receptor has a high affinity for apoE)

Question 23

What is the relevence of the LDL half life?

Answer 23

Half life of LDL in the blood is much longer than VLDL or IDL making LDL more susptible to oxidative damage.

Oxidised LDL taken up my macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques.

Question 24

Summarise VLDL, IDL and LDL metabolism.

Answer 24

Question 25

How do LDLs enter the cells?

Answer 25

LDL enters cells by **receptor mediated endocytosis**. Receptors / LDL complex taken into cell by **endocytosis** into endosomes. They fuse with **lysosomes** for digestion to release cholesterol and fatty acids

Question 26

How does LDL know which cells require cholesterol?

Answer 26

Cells requiring cholesterol express LDL receptors on plasma membrane. ApoB-100 on LDL acts as a ligand for these receptors. LDL-R expression is controlled by cholestrol concentration in cells.

Question 27

How is HDL synthesised?

Answer 27

Nascent HDL is synthesied by the **liver** and intestine (low TAG levels). HDL particles can also "bud off" from chylomicrons and VLDL as they are digested by LPL. Free apoA1 can also acquire cholestrol and phospholipids from other lipoproteins and cell membranes to form naschent-like HDL.

Question 28

How do HDLs mature?

Answer 28

Nascent HDL accumulate **phospholipids** and **cholestrol** from cells lining blood vessels. Hollow core progressively **fills** and particle takes on more **globular** shape. Transfer of lipids to HDL does not require enzyme activity.

Question 29

What is reverse cholesterol transport?

Answer 29

HDL have the ability to remove cholestrol-laden cells and return it to the liver. Importnt process for blood vessles as it reduces likelyhood of foam cells and atherosclerotic plaque formation. ABCA1 protein within cells facilitates transfer of cholestrol to HDL. Cholestrol then convertd cholestrol ester via LCAT.

Question 30

What is the fate of mature HDLs?

Answer 30

Mature HDL taken up by liver via specifc transporters. Cells requiring additonal cholestrol (e.g. steroid hormone synthesis) can also utilise scavenger recepotr (SR-B1) to obtain cholestrol from HDL. HDL can also exchnage cholestrol ester for TAG with VLDL via sction of cholestrol exchange transfer protein (CETP).

Question 31

Summarise HDL metabolism.

Answer 31

Question 32

What are the main functions of the lipoproteins? (chylomicrons, VLDL, IDL, LDL, HDL)

Answer 32

_Chylomicrons_: Transport **dietary** triacylglycerol from the intestine to tissues such as adipose. _VLDL_: Transport of triacylglyceril **synthesised** in **liver** to adipose tissue for storage. _IDL_: Short lived **precursors** of LDL. Transport of cholestrol synthesised in the liver to tissues. _LDL_: Transport of cholestrol **synthesied** in **liver** to tissues. _HDL_: Transport of **excess** cholestrol from cells to **liver** for **disposal** as bile salts and to cells requiring **aditional** cholestrol.

Question 33

What are hyperlipoproteinaeminas?

Answer 33

This is when there are raised plasma levels of one or more lipoproteins. They are caused by either over-production or under-removal wich is causes by defects in: * Enzymes * Receptors * Apoproteins

Question 34

How many classes of hyperlipoproteinaemias are there? Which ones are most significant?

Answer 34

There are six main classes of hyperlipoproteinaemias. The three main types are: **Type I:** This is caised by defective **liporpotein lipase** (LPL). It causes there to be chypomicrons in fasting plasma and it not linked with coronary heart disease. **Type IIa:** Caused by defective **LDL receptor**. Assosiated with coronary artery disease that may be severe. **Type III:** Cause by defective **apoprotein (apoE)**. Raised IDL and chylomicron reminants. Associated with coronary artery disease. It is rare.

Question 35

What are the clinical signs of hypercholesterolaemia?

Answer 35

High level of **cholestrol in blood.** Cholestrol depositions in various areas of the body. **Xanthelasma** - yellow patches on eyelids. **Tendon Xanthoma** - Nodules on tendon. **Corneal arcus** - abvious white circle around eye. Common in older people but if present in young could be a sign of hypercholesterolaemia.

Question 36

How is raised serum LDL associated with atherosclerosis?

Answer 36

Question 37

How is a plaque formed?

Answer 37

Question 38

What is the first approach treatment of hyperlipoproteinaemias?

Answer 38

**Diet**: Reduce cholesterol and saturated fat in diet and increase fibre intake (fibre sequesters bile salts) **LIfestyle**: Increase exercise and stop smoking to redice cardiovascular risk

Question 39

What is the second level response used to treat hyperlipoproteinaemias?

Answer 39

Drugs! **Statins**: Reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin. **Bile salt sequestrants:** Bind bile salts in GI tract. Forces liver to produce more bile acids using more cholesterol e.g. Colestipol

Question 40

How do statins work?

Answer 40

They block the first enzyme in pathway so reduce synthetic capacity of cholesterol.

Question 41

Why do statins have side effects?

Answer 41

Because statins block the effect of an enzyme that is high up in the pathway. This means that few intermediates are made. These intermediates could have other uses.

Question 42

What cholesterol tests can you do?

Answer 42

**Total cholestrol** (TC) - ideally 5 mmol/L or less. **Non HDL-Cholestrol** (total cholestrol minus HDL cholestrol) - Ideally 4 mmol/L or less. **LDL-Cholestrol** (LDL-C) - Ideally 3 mmol/L or less. **HDL-Cholestrol** (HDL-C) p Ideally over 1mmol/L for men and 1.2mmol/L for women. **Total chlesterol : HDL-C ratio** - a ratio of above 6 is considered high risk - the lower the ratio the better. **Triglyceride** (TG) Ideally over 2 mmol/L in fasted sample .