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Biochemistry > Lipoproteins and Cholesterol > Flashcards

Lipoproteins and Cholesterol Flashcards

1
Q

How are fatty-acids synthesised?

A

From acetyl-CoA and malonyl-CoA, carried out by fatty acid synthase. Reduction by NADPH to make the saturated fatty acid.

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2
Q

What is the structure of fatty acids and what part of it will participate to make lipids and store energy?

A

Large chain of carbon atoms bonded with hydrogen atoms. One end has a COOH group, which is the reactive portion that participates to make lipids.

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3
Q

What synthesises cholesterol and what else does it do with cholesterol?

A

The liver is central to the regulation of cholesterol levels in the body. Not only does it synthesize cholesterol for export to other cells, but it also removes cholesterol from the body by converting it to bile salts and putting it into the bile where it can be eliminated in the feces.

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4
Q

What is cholesterol and what is the structure?

A

A lipid. Structure consists of four fused hydrocarbon rings. Hydrocarbon at one end and hydroxyl tail at the other end.

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5
Q

Why is cholesterol known as ‘sterol’?

A

It is made out of an alcohol and steroid.

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6
Q

How is cholesterol metabolised?

A

Oxidised by the liver into a variety of bile acids. Mainly converted into coprostanol - nonabsorbable sterol that is excreted in the faeces.

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7
Q

How are cholesterol and TAGS transported in the bloodstream?

A

Mature chylomicrons.

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8
Q

What does the hydrophobic core of ‘phospholipid transfer proteins’ contain?

A

Cholesterol esters and TAGs.

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9
Q

What is LCAT and what does it do and what are they transported by?

A

Lecithin Cholesterol Acyl Transferase. Catalyses transfer of fatty-acids to create cholesterol esters. Transported in lipoproteins/PLTP

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10
Q

What is CETP, what is it synthesised by, what does it do and what is it transported by?

A

Cholesterol ester transfer protein. Synthesised by liver, small intestine, adipose tissue and macrophages. Binds to lipid molecules and facilitates association with lipoproteins. Promotes transfer of cholesterol esterase’s from HDL to VLDL particles.

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11
Q

What is PLTP?

A

Phospholipid transfer protein, interchange of phospholipid molecules between lipoproteins, especially to HDL.

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12
Q

Size and composition of Chylomicron (major lipoprotein group)

A

500nm. 1-4% cholesterol. 86-94% triglyceride.

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13
Q

Size and composition of VLDL (very low density)

A

43nm. 15-20% cholesterol. 55-65% triglyceride.

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14
Q

Size and composition of IDL (intermediate density)

A

27nm. 25-45% cholesterol. 25-40% triglyceride.

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15
Q

Size and composition of LDL (low density)

A

22nm. 40-55% cholesterol. 6-12% triglyceride.

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16
Q

Size and composition of HDL (high density)

A

8nm. 10-25% cholesterol. 3-8% triglyceride.

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17
Q

Explain the process of lipoprotein (chylomicron) metabolism.

A

From the small intestine, the chylomicron molecule goes to adipose/muscle cells and lipoprotein lipase removes TAGS from the chylomicron to HDL (as it contains triglycerides and cholesterol, but the free fatty acids remain in the adipose cells). HDL forms CM remnants which go into the liver (cholesterol goes into bile duct). Liver releases VLDL which goes to adipose/muscle cells and once again lipoprotein lipase breaks it down, releasing free fatty acids in the adipose cells, and releasing cholesterol to make HDL again, or VLDL becomes IDL (which can also release its triglycerides to HDL, and also gain cholesterol esters from HDL). IDL goes into the liver and stays there, or hepatic lipase breaks it down to form LDL, which then attaches to LDL receptors, which are found on the cells of peripheral tissues.

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18
Q

Where does mature chylomicron go?

A

Bloodstream.

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19
Q

What are TAGs converted too and by which enzyme?

A

Monacylglycerols + free fatty acids. Via pancreatic lipase.

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20
Q

What are FC’s and how are they formed? What are they packaged with to make what?

A

Free cholesterols/plant sterols converted from cholesterol ester’s via esterase. Packaged with monoacylglycerol + FFA + bile salts. Makes mixed micelles.

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21
Q

Where are chylomicrons found and what are they composed off, and what do they do?

A

Chylomicrons are found in the blood and lymphatic fluid. Composed of lipid and proteins. They serve to transport fat from its port of entry in the intestine to the liver and to adipose (fat) tissue.

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22
Q

What protein is unique and contained in chylomicrons? What other proteins does it acquire?

A

apoB48. Also acquires apos C1, C2, C3 and E.

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23
Q

How does chylomicron promote TAG removal from the bloodstream?

A

Once chylomicron is in the bloodstream, apo C2 activates lipoprotein lipase, promoting TAG removal.

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24
Q

What protein also regulates the process of tag removal, and what enzymatic process does it inhibit?

A

Regulated by apo C3. Inhibits lipoprotein lipase activity.

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25
Q

As TAGs are removed from the bloodstream, what does apo E act as and what does it interact with?

A

Apo E acts as a ligand (as it is now more accessible), to interact with hepatic receptors, LDLR and LDP.

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26
Q

How do apos C1 and C2 inhibit the uptake of chylomicrons/remnants by the liver?

A

Prevent apo E from binding to hepatic receptors.

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27
Q

Where are plant sterols transported into and by what transporter?

A

Transported into intestinal cell by the intestinal sterol transporter (NPC1L1).

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28
Q

What are TAGs reformed and bundled with and what do they go into? Where do they enter?

A

apo B48, into a chylomicron. Enter the lymph via the microsomal transfer protein (MTP) and enter the bloodstream.

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29
Q

What is the main source of cholesterol?

A

Internal synthesis, not dietary.

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30
Q

Where are TAGs and cholesterol esters now found after being removed from chylomicrons?

A

Liver.

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31
Q

VLDL has apo B100, which is structural, but also acts as a…

A

ligand.

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32
Q

How are TAGs added in VLDL formation?

A

Via microsomal triacylglycerol transfer protein (MTP).

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33
Q

What is the rate of synthesis for VLDL formation in the liver determined by?

A

By the delivery of fatty-acids to the liver.

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34
Q

What governs the removal rate of TAGS (and via what enzyme) from VLDL after it is released into the bloodstream?

A

Enzyme: lipoprotein lipases. Governed by: apos C1, C2, C3 A5 and E.

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35
Q

What acts to inhibit CETP and what does this reduce the transfer off?

A

Apo C1. Reduces TAG transfer to other lipoproteins.

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36
Q

What apo allows more TAG to be delivered to extra-hepatic tissues and why? When is this useful?

A

Apo C3, as it inhibits lipolipase activity, particularly in the liver, so allows more TAG to be delivered to extra-hepatic tissues. This is useful if energy demand increases as it is direct oxidation by muscles.

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37
Q

Which Apo activates lipoprotein lipase and what activity does this promote?

A

Apo C2. Promotes TAG removal.

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38
Q

What does Apo A5 promote the removal of and how?

A

VLDL and chylomicron remnants, by facilitating binding to lipoprotein lipase.

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39
Q

What is only produced in the liver, has very low levels in plasma, but is recycled avidly and has a stabilising role?

A

Apo A5.

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40
Q

What is left after TAGS and apo C1 and C2 proteins are lost? And what binds to hepatic receptors as a result?

A

LDL. Apo E is able to bind to hepatic receptors.

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41
Q

What is the main Apo protein in LDL?

A

Apo B100.

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42
Q

What receptor removes LDL from the blood, and what apo proteins does this receptor bind with?

A

Hepatic LDL receptor (LDLR). Binds with Apo B100 or Apo E.

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43
Q

What are high levels of LDL associated with in the heart?

A

Atheromatous plaques in arteries.

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44
Q

During the LDL receptor mechanism, where do receptors cluster into?

A

Cluster into these clathrin-coated pits.

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45
Q

What is clathrin?

A

A protein associated with vesicle formation.

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46
Q

When LDL binds to the receptor, what happens to this complex?

A

Buds off to form an endosome with an acidic internal environment, and LDL is released into the cytoplasm of the cell where it can be processed and used (in peripheral cells- internal source of cholesterol to avoid cell having to manufacture its own). And the receptor is recycled back to the cell surface.

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47
Q

How do mutations affect this process (LDL receptor mechanism) and what is the term for this?

A

Increased levels of LDL in the bloodstream - hypercholesterolaemia.

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48
Q

How are the number of LDL receptors on the cell surface regulated?

A

The amount of intracellular cholesterol regulates the rate of cholesterol synthesis and the no. of LDL receptors on the cell surface.

49
Q

What processes modify the LDL that is left in circulation to enhance take-up by scavenger receptors in the macrophage foam cells?

A

Glycations, oxidation (and other reactions). These form a key stage in atheroma formation (which links to diabetes).

50
Q

Why can processes modify the LDL that is left in circulation?

A

As it in its small dense form.

51
Q

What is the first step in an atheroma developing and who are they common in?

A

Fatty streaks, common in young adults and children.

52
Q

What is the second step of a developing atheroma?

A

Foam cells develop - macrophages which have migrated through endothelial lining engulf cholesterol, also further lipid uptake and smooth muscle proliferation.

53
Q

What is the 3rd step of a developing atheroma?

A

Large lipid core develops, phospholipase type A2 circulates in plasma and also promotes LDL uptake via the scavenger receptors (type B1/ Class A).

54
Q

What is the 4th step of a developing atheroma?

A

Fibrous cap forms and calcification may occur causing hardening. Rupture or damage to the cap can lead to clotting processes and occlusion of artery.

55
Q

What is the main structural apoprotein in HDL, where is it synthesised and how many are found per particle of HDL?

A

Apo A1. Synthesised in the liver and intestines. Between 4 and 7 molecules of ApoA1 per particle of HDL, which produces a discoidal HDL particle.

56
Q

After a discoidal HDL particle is produced, what does it begin to gather? What does ApoA1 bind LCAT too, to elicit which process and to create what?

A

Begins gathering free cholesterol and phospholipids from cells (inc foam cells). ApoA1 binds LCAT to the HDL, which is then able to facilitate esterification of the cholesterol to create more cholesterol esters (CE).

57
Q

How does the surface area of a HDL particle increase and what does this allow?

A

Highly hydrophobic particles sink to the core of the HDL particle, increasing available surface area for free cholesterol to be taken on.

58
Q

Where is HDL taken where CE’s can be removed/processes/exchanged to VLDL’s? And what are VLDL’s converted to and taken up by the liver?

A

The liver. VLDL converted to LDL.

59
Q

HDL has an anti-atherogenic effect, what does this mean?

A

Preventing or inhibiting atherogenesis antiatherogenic effects (where the end result is a fatty streak).

60
Q

Where is esterified cholesterol (in HDL) transferred and taken up to?

A

Can be transferred to other lipoproteins and taken up by the liver and HDL can be taken up directly by the liver.

61
Q

What do increased blood levels of LDL implicated in the development of?

A

Atheromatous plaques.

62
Q

What reduces atheromatous plaques?

A

HDL.

63
Q

Is there a positive correlation between plasma cholesterol levels and risk of CHD?

A

Yes.

64
Q

Do individuals that have a higher proportion of HDL compared with total cholesterol have a lower risk of CHD?

A

Yes.

65
Q

Why is HDL better than LDL?

A

It transports cholesterol to liver to be expelled.

66
Q

What is Q-risk calculator?

A

The QRISK algorithm calculates a person’s risk of developing a heart attack or stroke over the next 10 years. It presents the average risk of people with the same risk factors as those entered for that person and has been developed by the NHS.

67
Q

What does Frederickson Classification recognise? And how were lipid fractions analysed?

A

Recognises 5 different types based on proportion of different lipoproteins present. Analysis of fractions were done by ultra-centrifugation or electrophoresis.

68
Q

How does ultracentrifugation separate lipoproteins?

A

Centrifuge uses a ‘salt’ gradient, lipoproteins separate on basis of density.

69
Q

What are the benefits of electrophoresis over ultracentrifugation?

A

Easier. Movement in electrical field depends on charge on lipoproteins. Cellulose acetate strips. After EP, stain strips with a fat-soluble stain, measuring optical density by scanning densitometer. Quantify. Chylomicrons do not move because of size; other move to anode (+ve).

70
Q

What pH is EP done at and why?

A

8.6. At high pH there are few protons in solution.

71
Q

At a pH of 8.6 what are the charged amino acid side chains like? What is their overall charge and therefore what do they move towards?

A

COO- (Asp, Glu)

NH2 (Lys, Arg, His). Overall negative charge, move towards anode (+ve).

72
Q

What is the Friedewald formula? And what is it used for?

A

The current diagnostic assessment of lipid levels. LDL chol. = total chol. - HDL chol. - TAG/2.2

73
Q

Why are patients asked to fast for 18 hours pre-analysis of TAG levels?

A

TAG levels reflect recent dietary intake.

74
Q

What is the desirable range for cholesterol?

A

< 5.2mmol/L

75
Q

If the patient is on lipid-lowering treatment/high risk status, what is their desirable cholesterol levels be?

A

< 4.0 mmol/L

76
Q

What is the desirable triacylglycerides level (when fasting)?

A

< 1.7 mmol/L

77
Q

What should the desirable ratio of total and HDL cholesterol be?

A

Total cholesterol : HDL cholesterol < 4

78
Q

In spectrophotometric methods what does cholesterol esterase convert ‘cholesterol ester + H20’ too, releasing what as a by product?

A

Cholesterol. Fatty acid as by product.

79
Q

In spectrophotometric methods what does cholesterol oxidase convert ‘cholesterol’ too, releasing what as a by product?

A

H2O2. And 02 –> Cholesterol-4-en-3-one as a by product.

80
Q

In spectrophotometric methods what does peroxidase convert ‘H202’ too, releasing what as a by product?

A

Coloured product (with process ending at this point). 4-aminophenazone + phenol as by products.

81
Q

In spectrophotometric methods what does lipase convert ‘TAG + 3H20’ too, releasing what as a by product?

A

Glycerol. 3 Fatty acids as by product.

82
Q

In spectrophotometric methods what does glycerol kinase convert ‘glycerol’ too, releasing what as a by product?

A

Glycerol-3-phosphate. ATP –> ADP as a by product.

83
Q

In spectrophotometric methods what does glycerophosphate oxidase convert ‘glycerol 3-phosphate’ too, releasing what as a by product?

A

H202. O2 –> dihydroxyacetone phosphate as a by product.

84
Q

In spectrophotometric methods what does peroxidase convert ‘H2O2’ too, releasing what as a by product?

A

Coloured product (with process ending here). 4-aminophenazone + 4-chlorophenol.

85
Q

What is the only additional step placed at the beginning of the spectrophotometric process of turning Cholesterol Ester + H20 into ‘coloured product’, between cholesterol and HDL-c?

A

Step to bind LDL, VLDL and CM e.g. an antibody is added that specifically binds Apo B.

86
Q

What What is the only additional step placed at the beginning of the spectrophotometric process of turning Cholesterol Ester + H20 into ‘coloured product’, between cholesterol and LDL-c?

A

A step to prevent HDL, VLDL and CM reacting to produce colour change, e.g. selective ‘quenchers’ or surfactants.

87
Q

What are secondary causes of hyperlipidaemia?

A

Obesity, DM (type 2), hypothyroidism, corticosteroids, renal diseases, chronic renal failure, drugs, alcohol excess.

88
Q

In obesity, what are levels of cholesterol and TAG like? And how is this triggered?

A

High. Triggers caused by increase in VLDL.

89
Q

In hypothyroidism, what are levels of cholesterol and TAG like? And what is it caused by?

A

Chol. is high. TAG is high or normal. Caused by reduced LDLR and LRP mediated uptake of LDL.

90
Q

In type 2 DM, what are levels of cholesterol and TAG like? And what causes it?

A

High. Caused by high VLDL due to insulin resistance as insulin suppresses release of fatty acids from adipose tissues and encourages hepatic VLDL production.

91
Q

In excessive alcohol consumption, what are cholesterol and TAG levels like and what causes this?

A

High. Caused by high VLDL, which is caused by increased fatty-acid production.

92
Q

What is increased VLDL associated with and why?

A

Increased cholesterol, as it is the pre-cursor to LDL.

93
Q

What are causes of primary lipidaemia?

A

Inherited diseases, monogenic or polygenic mutations, hypercholesterolaemia, hypertriglyceridaemia.

94
Q

What is an example of polygenic inheritance in hyperlipidemia?

A

Familial hypercholesterolaemia.

95
Q

What is familial hypercholesterolaemia (FH) due too and what does it cause?

A

Defective LDLR-mediated endocytosis, which causes exceptionally high cholesterol levels.

96
Q

How many mutations are known and how many out of 500 worldwide are heterozygous for a mutation/autosomal dominant (getting disease from one parent as mutated gene is dominant)?

A

900 mutations are now known. 1 in 500 worldwide.

97
Q

Are homozygous individuals affected by FH? How does the condition present in heterozygotes?

A

Very severely, can be soon after infancy. Usually some sign of arterial disease before age 50 in heterozygotes.

98
Q

What are the clinical manifestations (signs/symptoms) of FH?

A

Varies, unhealthy lifestyle choices, mutation, male/female

99
Q

What several factors provide a definite diagnosis of FH?

A

First (50% genetic link) or second degree (25% genetic link) relative with FH. Total cholesterol of >7.5mmol/L (adults) >6.7mmol/L (children).

OR LDL > 4.9mmol/L (adults) > 4.0mmol/L (children)
Plus tendon xanthomas (yellow patch on skin caused by deposition of lipids).

100
Q

How is FH treated?

A

Statins.

101
Q

What is familial defective apoprotein B100?

A

An autosomal recessive disorder where the apoB100 domain is defective (domain is recognised by LDLR).

102
Q

Is Apo-E’s function affected in familial defective apoprotein B100 disorder?

A

Apo-E mediated uptake normal.

103
Q

What are the cholesterol levels like in homozygous individuals with familial defective apoprotein B100? What treatment do individuals with the disorder respond well too?

A

> approx 7.5mmol/L. Statin treatment.

104
Q

What is the dietary treatment of hyperlipidaemia?

A

Reduce calorie intake to achieve ideal body weight, moderate alcohol intake, reduce total fat intake to provide only about 30% of calories, reduce saturated fat intake to provide only 30% of total fat intake and increase dietary fibre intake.

105
Q

How many plant sterols have been identified and which 3 are the most abundant?

A

Over 40. Sitosterol, campesterol and stigmasterol.

106
Q

Where are plant sterols naturally present in? What else can occur in even smaller quantities in many of the same sources?

A

In small quantities in many fruits, vegetables, nuts, seeds, cereals, legumes, vegetable oils and other plant sources. Plant stanols.

107
Q

What do plant sterols and stanols (phytosterols) structurally resemble and what are they both essential components off?

A

Essential components of plant cell membranes and structurally resemble cholesterol.

108
Q

What sort of sterol is cholesterol?

A

Exclusively an animal sterol.

109
Q

What is the main benefit and purpose of dietary plant stanols and sterols and why?

A

Cholesterol-lowering. They compete with cholesterol for absorption in the digestive system.

110
Q

Name some examples of phytosterols present in food.

A

Corn oil, sunflower oil, safflower oil, soybean oil, olive oil, almonds, beans, corn, wheat, palm oil, lettuce, banana, apple, tomato.

111
Q

Even though people are consuming phytosterols every day, what is the problem that is preventing cholesterol from lowering?

A

The amounts consumed are not great enough to have significant blood cholesterol-lowering effects.

112
Q

How has the challenge of incorporating larger amounts of plant stanols and sterols into the diet been overcome? Which foods are typically used?

A

By modifying plant stanols and sterols structurally to form stanol and sterol esters which can be easily incorporated into fat-containing foods without losing their effectiveness in lowering cholesterol. Margarine and yoghurt are typical foods used.

113
Q

By how much do phytosterols inhibit the absorption of cholesterol in the small intestine (when in its ester form/appropiate quantities)? And how much can this lower LDL-c by?

A

By up to 50%, which in turn can lower LDL blood cholesterol by up to 14%.

114
Q

Why will patients who are on statin therapy achieve further decreases in their blood cholesterol levels when using phytosterol esters?

A

Because statins work to decrease blood cholesterol by a different mechanism.

115
Q

How do statins work when decreasing blood cholesterol? What is the enzyme

A

Block an enzyme (HMG coenzyme A reductase) in the body that is involved in the production of LDL cholesterol, especially in the liver. Statins are the most effective group of drugs for lowering the levels of LDL cholesterol.

116
Q

What are the side effects of statins?

A

Muscle-related symptoms in 5% of patients. Liver disruption. Sleeping problems.

117
Q

Why are statins effective but not a panacea?

A

14% of patients taking statins still experience a cardiac event.

118
Q

How is hyperlipidaemia assessed?

A

By lab tests.

119
Q

What do positive lifestyle modification combined with statins and plant stanols reduce the risk off?

A

CVD.

Biochemistry (7 decks)

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