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Sem 2 - MEH > Lipid Transport > Flashcards

Lipid Transport Flashcards

1
Q

Lipids are insoluble, Why is this a problem?

A

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

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2
Q

What is a cholesterol ester?

A

A cholesterol with a fatty acid added to it.

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3
Q

How are lipids transported in the blood?

A

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.

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4
Q

What should total Cholestrol in blood be?

A

Total cholestrol should be under 5 mmol/L

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5
Q

What is the most common head group of phospholipids?

A

Choline to make phosphatidylcholine.

Inositol is another head - forms phosphatidylinositol.

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6
Q

What different shaped structures can phospholipids form?

A
  • Bilayer sheet
  • Liposome
  • Micelle
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7
Q

Where is most cholesterol synthesised?

A

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

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8
Q

Why is cholestrol essential?

A
  • Cholestrol is an essential component of membranes (modulates fluidity).
  • Precursor of steroid hormones
    • Cortisol
    • Aldosterone
    • Testosterone
    • Oestrogen.
  • Precursor of bile acids.
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9
Q

How is cholestrol transport?

A

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.

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10
Q

What is the structure of a lipoprotein?

A
  • Peripheral Apolipoproteins (apoC, apoE)
  • Integral Apolipoproteins (apoA, apoB)
  • Phospholipids monolayer with small amount of cholestrol
  • Cargo consisting of:
    • Triacylglycerol
    • Cholestrol esters
    • Fat soluble vitamins
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11
Q

What are the five classes of lipoproteins?

A

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.

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12
Q

How big are each of the lipoproteins?

A
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13
Q

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

A

Density obtained by flotation ultracentrifugation.

Particle diameter is inversely proportional to density

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14
Q

What are Apolipoproteins?

A

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)

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15
Q

What are the most important apolipoproteins?

A

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

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16
Q

What are the two roles of apolipoproteins?

A

Structural: Packaging a water insoluble lipid.

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

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17
Q

How are chylomicrons metabolised?

A

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.

18
Q

What is lipoprotein lipase?

A

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.

19
Q

How are VLDLs metabolised?

A

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.

20
Q

How are IDL and LDL metabolised?

A

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).

21
Q

Why are LDL bad?

A

Because they promote cardiovascular disease.

22
Q

What are the functions of LDL?

A

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)

23
Q

What is the relevence of the LDL half life?

A

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.

24
Q

Summarise VLDL, IDL and LDL metabolism.

A
25
Q

How do LDLs enter the cells?

A

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

26
Q

How does LDL know which cells require cholesterol?

A

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.

27
Q

How is HDL synthesised?

A

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.

28
Q

How do HDLs mature?

A

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.

29
Q

What is reverse cholesterol transport?

A

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.

30
Q

What is the fate of mature HDLs?

A

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).

31
Q

Summarise HDL metabolism.

A
32
Q

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

A

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.

33
Q

What are hyperlipoproteinaeminas?

A

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
34
Q

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

A

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.

35
Q

What are the clinical signs of hypercholesterolaemia?

A

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.

36
Q

How is raised serum LDL associated with atherosclerosis?

A
37
Q

How is a plaque formed?

A
38
Q

What is the first approach treatment of hyperlipoproteinaemias?

A

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

39
Q

What is the second level response used to treat hyperlipoproteinaemias?

A

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

40
Q

How do statins work?

A

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

41
Q

Why do statins have side effects?

A

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.

42
Q

What cholesterol tests can you do?

A

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 .

Sem 2 - MEH (22 decks)

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