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IMS topic 4 - Lipids > Cholesterol & lipoproteins > Flashcards

Cholesterol & lipoproteins Flashcards

1
Q

Give 3 functions of lipids

A
  • Energy storage
  • Major components of cell membranes
  • Required to solubilise fat soluble vitamins
  • They are biosynthetic precursors (e.g. steroid hormones from cholesterol)
  • Signalling molecules
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2
Q

Where does cholesterol come from?

A

The diet

Synthesised in the liver

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3
Q

What are lipoproteins?

A

Particles found in plasma that transport lipids and cholesterol because it is insoluble in blood plasma

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4
Q

What is the role of Chylomicrons?

A

Transport of dietary fats (triglycerides and cholesterol) from the intestine to tissues

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5
Q

What is the role of VLDL? (very low density lipoprotein)

A

Transport lipids made in the liver to peripheral tissues

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6
Q

What is the role of LDL?

A

Provide cholesterol for peripheral tissues, the main cholesterol carrier.

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7
Q

What is the role of HDL?

A

Made in the blood, transports cholesterol to the liver from peripheral tissues

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8
Q

What is the basic structure of lipoproteins

A

They have an external monolayer containing phospholipids, cholesterol and apopliproteins. Cholesterol esters and triacylglycerols are located in the particle core.

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9
Q

What are apolipoproteins and what is their role?

A

Specific protein strands embedded in the surface of lipoproteins. They are different in each lipoprotein ad determine the start and end points for cholesterol transport to particular tissues to distinguish function.
LIPID + APOPLIPOPROTEIN = LIPOPROTEIN

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10
Q

What is the role of ApoA and where is it present?

A

Mediates efflux of cholesterol from peripheral cell and influx to the liver (present in HDL)

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11
Q

What is the role of ApoB?

A

Recognises apoB/E to facilitate LDL uptake

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12
Q

What is the role of ApoC?

A

Activator of lipoprotein lipase, transferred between lipoproteins

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13
Q

What is the role of ApoE?

A

Stabilises VLDL for cellular uptake, a ligand for the apoB/E receptor.

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14
Q

Where are apolipoproteins synthesised and what regulates this?

A

In the intestine, regulated by dietary fat intake

In the liver, regulated by hormones and drugs

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15
Q

What is the main general role of apolipoproteins?

A

They regulate key enzymes in lipoprotein metabolism and ar ligands for interaction with lipoprotein receptors, targeting lipoproteins to the correct tissues

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16
Q

What is the structure of LDL?

A

A surface monolayer of phospholipids and free cholesterol and a single molecule of apolipoprotein B which encircles the lipoprotein, surrounding a hydrophobic core of MAINLY cholesteryl esters and some triglycerides

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17
Q

Is LDL proinflmmatory in itself?

A

No, it is oxidised and then becomes pro inflammatory and promotes formation of fatty acid deposits in arteries

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18
Q

What is the structure of HDL?

A

Same essential structure as LDL; surface monolayer of phospholipids and free cholesterol and a hydrophobic core consisting mainly of cholesteryl esters and with some triglyceride.
HDL parties are smaller and contain different apolipoproteins, mainly app A-I and apo AII

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19
Q

What is the difference between the apoliporproteins in HDL and LDL

A

In HDL they have properties that protect the lipids against oxidative modification, making it resistant to oxidation and giving it anti-inflammatory properties == good cholesterol

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20
Q

What is the role of chylomicrons and how are they recycled?

A

They are made in the intestine. They transport triglycerides and cholesterol int he blood, triglycerides are hydrolysed by the lipoprotein lipase to fatty acids that are used for energy production and storage. Chylomicrons shrink and their remnants are transported back to the liver

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21
Q

What is the role of VLDLs and how are they recycled?

A

Made in the liver. Transport lipids to target tissues. Acted on by lipase to release fatty acids that are used for energy production/storage.
VLDL remnants remain in the blood, become LDLD that are then taken up by target cells by the LDL receptor and are digested in the lysosome to release cholesterol

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22
Q

What is the role of HDLs?

A

Remove cholesterol from tissues. They are synthesised in the blood and extract cholesterol from cell membranes and take it back to the liver.

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23
Q

How does the liver dispose of large quantities of cholesterol?

A

In the form of bile salts

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24
Q

What is the role of membrane bound lipoprotein receptors?

A

They allow cholesterol entry to hepatic (liver) cells and peripheral cells (blood cells)

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25
Q

What does the LDL receptor (apoB/E receptor) bind?

A

apoB-100 or apoE

26
Q

How is LDL receptor gene expression regulated?

A

Intracellular cholesterol concentration

27
Q

What happens when LDL binds to the receptor?

A

An endosome is formed, ingesting the receptor into a “clathrin coated pit”. The vesicle enters the cell and loses the clathrin coating at pH 7. LDL is separated from he receptor in the endosome and the receptor is recycled to the membrane (if there is demand for it). Cholesterol is released and used as required

28
Q

What is clathrin?

A

A protein on the cell membrane that forms coated vesicles

29
Q

What is cholesterol used for in cells?

A 
Membrane synthesis
Steroid hormone synthesis
Structural component of membranes
Synthesis of bile acids
Synthesis of fat-soluble vitamins
30
Q

What suppresses LDL receptor synthesis?

A

High intracellular levels of cholesterol, to prevent excessive cholesterol uptake

31
Q

How does HDL protect against atherosclerosis?

A

Through reverse cholesterol transport (returns cholesterol to the liver)

32
Q

How does the liver get rid of cholesterol?

A

Secretion in bile and excretion by the intestine

33
Q

What are mutations affecting the LDL receptor associated with?

A

Familial hypercholesterolaemia - high levels of cholesterol through inherited disease

34
Q

What is the issue with cells lacking functional LDL receptors?

A

They cannot take up LDL so there is excess in the blood and more chance of atherosclerosis

35
Q

Give an examples of another genetic defect causing high cholesterol?

A

Defects in structure of apoplipoproteins = impaired binding of LDL to cell surface receptor

36
Q

What is the structure of Lipoprotein (a)?

A

Long polypeptide chain linked to appB-100. Has multiple “kringle” structure (looks like a danish pastry) (small swirls)

37
Q

What are high levels of lipoprotein a related to?

A

High risk of cardiovascular disease

38
Q

Is apopliportein a genetically determined? Is there a wide variation in size?

A

Yes

YEs

39
Q

What is a major constituent of atherosclerotic plaque?

A

cholesterol enriched LDL

40
Q

What can cerebral atherosclerosis cause?

A

Stroke, cerebral haemorrhage

41
Q

What can peripheral atherosclerosis cause?

A

Pain, ischemia, ulceration, gangrene

42
Q

What level of serum cholesterol should a healthy adult have?

A

175mg/100ml

43
Q

What level of serum cholesterol should a healthy newborn have?

A

25mg/100ml

44
Q

What level of serum will a familial hypercholesterolaemia heterozygote and homozygote have?

A 
heterozygote = 300mg/100ml
homozygote = 700mg/100ml
45
Q

Are mammals resistant to atherosclerosis ?

A

Yes, they have similar cholesterol levels to a newborn human

46
Q

What is the key enzyme in the cholesterol synthetic pathway?

A

HMG-CoA reductase

47
Q

Which two organs primarily control blood cholesterol levels and how?

A

Liver; produces cholesterol and bile acids

Intestine; absorbs cholesterol from food and bile

48
Q

Describe the cholesterol synthetic pathway

A

HMG-CoA reductase enzyme coverts HMG-CoA to MEVALONATE (an important intermediate). This is converted to IPP and then FPP (isoprenoid that carries out prenylation) and then Squalene and then cholesterol

49
Q

Which two organs are targets in the treatment of familial hypercholesterolemia?

A

liver

intestine

50
Q

What is the role of statins? How do they work?

A

They prevent cholesterol synthesis in the liver by inhibiting HMG-CoA reduxatse which reduces the levels of the intermediate mevalonate and therefore reduce synthesis of cholesterol.
Lower levels of cholesterol in the cell means more LDL receptors are created so there is a higher uptake from the blood

51
Q

Define pleiotropic effects?

A

effects other than what the drug was developed for

52
Q

Are pleiotropic effects in statins beneficial? Give some examples

A

Yes
Have equal benefits in patients with normal cholesterol in lowering chance of coronary heart disease
Improved endothelial dysfunction
Antioxidant properties
Inhibition of inflammatory responses
Stabilisation of atherosclerotic plaques by stabilising top layer of cells so blood can flower over safely

53
Q

What is the role of cholesterol absorption inhibitors? How?

A

prevent the uptake of cholesterol/LDL from the intestine

They contain plant steroids which are taken up more easily than cholesterol, so cholesterol remains in the gut

54
Q

What is the role of fibrates in reducing the risk of atherosclerosis?

A

They reduce triglyceride levels and increase HDL

55
Q

What is the role of bile salts?

A

They break up fats, adding their digestion and absorption. They are made from cholesterol.

56
Q

What are isoprenoids? Give some examples

A

Lipid molecules that are other intermediates of mevalonate. Hydrophobic and are required for prenylation.
E.g. farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)

57
Q

What is prenylation? Why does it occur?

A

Prenylation is the process of a lipid tail becoming attached into intracellular signalling molecules called G-proteins (or GTPases), e.g. Was and Rho which are involved in gene expression.
G porteins floating in the cytosol cannot signal; isoprenoids attach them to the membrane to allow them to activate signalling pathways.

58
Q

How are Ras and Rho prenylated?

A

Ras is farnesylated and Rho is geranylgeranylated

59
Q

What is the role of statins in terms of prenylation?

A

They inhibit production of isoprenoids to stop prenylation, so G proteins cannot activate signalling pathways, so negative CVD effects are stopped

60
Q

What is PCSK9? How can this be used in treatment

A

A certain protease enzyme expressed by the liver which usually promotes intracellular degradation of LDL receptors and prevents recycling of LDL receptors to cell surface membrane. There are links between a mutation in PCSK9 and coronary heart disease due to gain/loss of function.
Some patients can’t take statins, so inhibition of this enzyme can reduce blood cholesterol levels.

61
Q

How does PCSK9 inhibition increase LDL uptake into cells?

A

PCSK9 attaches to LDL receptor with LDL and is taken up into the membrane in the vesicle. PCSK9 destroys the LDL receptor so it cannot be recycled and LDL stays in the blood.
PCSK9 inhibitor mops up PCSK9 and inhibits it from binding to the receptor = more recycling of receptors

62
Q

How are PCSK9 inhibitors administered to patients?

A

Injection

IMS topic 4 - Lipids (6 decks)

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