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Cardiovascular: pharmacology > Physiology and Pharmacology of Cholesterol and Lipid Metabolism > Flashcards

Physiology and Pharmacology of Cholesterol and Lipid Metabolism Flashcards

1
Q

In fat cells lipids are used for ___-.

A

In fat cells lipids are used for storage.

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2
Q

They also start the____ pathway for ____ and ____ molecules. They are ____ for these.

A

They also start the sympathetic pathway for hormones and signalling molecules. They are precursors for these.

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3
Q

because cholesteryl esters and triglycerides are non-polar, how are they transported in the blood?

A

in lipoproteins

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4
Q

Cardiovascular disease(atherosclerosis) is strongly associated with:

A
  • elevated LDL ( or particles rich in triglycerides)
  • decreased HDL
    i. e. they have a poor HDL/ total cholesterol ratio
  • it is the ratio that is more important than the total level of cholesterol in the plasma. The LDL is not simply calculated by doing total minus HDL as there are lots of other components such as triglycerides.
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5
Q

what are the 2 causes of dyslipidaemia?

A 
diet and lifestyle 
genetic factors (e.g. familial hypercholesterolaemia)
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6
Q

all lipoproteins consist of a ____ core containing ____ _____ and _____,
a _____ shell comprising a monolayer of _____ ______, p______ and one, or more apoproteins (apo)

A

a hydrophobic core containing esterified cholesterol and triglycerides
a hydrophilic shell comprising a monolayer of amphipathic cholesterol, phospholipids and one, or more apoproteins (apo)

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7
Q

what does the hydrophilic shell allow?

A

fir the lipoprotein to be carried in the plasma

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8
Q

what apoproteins do HDL particles contain?

A

apoA1 and A2

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9
Q

what apoproteins do LDL particles contain?

A

apoB-100

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10
Q

what apoproteins do VLDL particles contain?

A

apo B-100

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11
Q

what apoproteins do chylomicrons particles contain?

A

apoB-48

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12
Q

what is the diameter of HDL?

A

7-20 nM

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13
Q

what is the diameter of LDL?

A

20-30 nM

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14
Q

what is the diameter of VLDL?

A

diameter 3-80 nM

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15
Q

what is the diameter of chylomicrons?

A

100-1000 nM

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16
Q

what are the two functions of apo b containing LP?

A

They deliver triglycerides i) to muscle for ATP biogenesis and ii) adipocytes.

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17
Q

where are chylomicrons formed?

A

in intestinal cells

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18
Q

chylomicrons deliver _____ triglycerides

A

dietary - this means they are derived exogenously

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19
Q

VLDL particles are formed in ____ cells and transport triglycerides synthesised__ ____ ____ - the endogenous pathway.

A

VLDL particles are formed in liver cells and transport triglycerides synthesised in that organ - the endogenous pathway.

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20
Q

after digestion of triglyceride what do you end up with?

A

monoglycerides and free fatty acids

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21
Q

25% of cholesterol comes from ______ and the remaining 75% is______.

A

25% of cholesterol comes from dietary fat and the remaining 75% comes is secreted in the bile.

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22
Q

agents that cause the excretion of ___ cause the ______ of cholesterol

A

agents that cause the excretion of bile cause the excretion of cholesterol

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23
Q

Monoglycerides and long chain fatty acids enter largely by ______ ____

A

Monoglycerides and long chain fatty acids enter largely by passive diffusion

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24
Q

how does cholesterol enter the enterocytes?

A

by the NPC1L1 receptor

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25
Q

once the MG and C have entered the cell they are ____ and you get ____ synthesis and ______ esterification to form the ____ _____ . The TG and cholesterol then form chylomicrons.

A

once the MG and C have entered the cell they are reunited and you get triglyceride synthesis (these tend to form droplets in the cell) and cholesterol esterification to form the cholesterol ester.

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26
Q

what is lipidation?

A

the process by which apoB-48 is incorporated into the chylomicron

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27
Q

which protein mediates lipidation of chylomicrons?

A

microsomal triglyceride transfer protein

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28
Q

VLDL particles containing triglycerides are assembled in liver hepatocytes from free fatty acids derived from which two sources?

A

i) adipose tissue (particularly during fasting) (ii) de novo synthesis

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29
Q

To target triglyceride delivery to ____ and ____ tissue, chylomicrons and VLDL particles must be activated by the transfer of ____ from ___ particles.

A

To target triglyceride delivery to adipose and muscle tissue, chylomicrons and VLDL particles must be activated by the transfer of apoCII from HDL particles.

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30
Q

what is LPL?

A

Lipoprotein lipase (LPL) is a lipolytic enzyme that is associated with the endothelium of capillaries in adipose and muscle tissue

31
Q

____ greatly facilitates the binding of chylomicrons and VLDL (apolipoproteins) to the ____

A

ApoCII greatly facilitates the binding of chylomicrons and VLDL (apolipoproteins) to the LPL enzyme

32
Q

what is the action of LPL

A

hydrolyses the triglyceride core which allows the release of free fatty acids and glycerol which can enter muscle or adipose tissue

33
Q

after the action of LPL the ______ has not moved from the apolipoprotein. Particles depleted of_____ (but still containing ____ ____ ) are termed chylomicron and VLDL _____

A

At this stage the cholesterol has not moved from the apolipoprotein. Particles depleted of triglycerides (but still containing cholesteryl esters) are termed chylomicron and VLDL remnants

34
Q
  1. LPL causes chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism.
  2. The chylomicrons and VLDL dissociate from the LPL
  3. the _____is removed and accepted once more by the ____ particles in exchange for another ___ to the remnant. This is _____§.
A

LPL causes chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism.
The chylomicrons and VLDL dissociate from the LPL
the ApoCII is removed and accepted once more by the HDL particles in exchange for another APO to the remnant. This is apoE.

35
Q

what is the importance of apoe?

A

it provide a high affinity ligand for receptor mediated clearance .

36
Q
  1. The remnants return to the liver and are further metabolised by ____ _____
A

The remnants return to the liver and are further metabolised by Hepatic lipase

37
Q
  1. All ______- containing remnants and 50% of _____ containing remnants are cleared by receptor mediated endocytosis into hepatocytes
A

All ApoB48- containing remnants and 50% of apoB100 containing remnants are cleared by receptor mediated endocytosis into hepatocytes

38
Q
  1. The remaining apo____ - containing remnants lose further____ through hepatic lipase, they become smaller and enriched in ____ ____ and via ____ density lipoproteins (ILD) become ____ particles lacking apo___ and retaining solely apo____.
A

The remaining apoB100 - containing remnants lose further triglycerides through hepatic lipase, they become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (ILD) become LDL particles lacking apoE and retaining solely apoB100.

39
Q

how does the liver clear LDL?

A

receptor mediated endocytosis

40
Q

clearance of LDL particles is crucially dependent upon the _______ ____ expressed by the liver and other tissues. Clearance by liver is most important.

A

clearance of LDL particles is crucially dependent upon the LDL receptor expressed by the liver and other tissues. Clearance by liver is most important.

41
Q

The LDL receptors in the liver allow the ____ to dock with relatively ___affinity to the ______ membrane

A

The LDL receptors in the liver allow the LDL to dock with relatively high affinity to the hepatocyte membrane

42
Q

Within the cell at the ______, cholesterol ( C ) is released from the ____ ____ (CE) by _____.

A

Within the cell at the lysosome, cholesterol ( C ) is released from the cholesteryl ester (CE) by hydrolysis.

43
Q

The LDL receptor which was engulfed with the LDL and the receptor is now …….

A

returned back to the membrane

44
Q

released cholesterol into the lysosome of the liver cell causes: 3 things

A
  • inhibition of the enzyme which is responsible for the synthesis of cholesterol - HMG-Coa
  • also when cholesterol rises in the hepatocytes this causes the down regulation of LDL receptor presentation
  • also get the storage of cholesterol as cholesteryl ester.
45
Q

why is LDL the bad cholesterol?

A

the damages lining of blood vessel allows for the movement and uptake of LDL from the blood into the intima of the artery. - starts the atheroma pathway

46
Q

HDL has a key role in ____ excess _____ from cells by transporting it in ____ to the ___

A

HDL has a key role in removing excess cholesterol from cells by transporting it in plasma to the liver

47
Q

Only the liver has the capacity to eliminate cholesterol from the body (as cholesterol secreted into ___, or used to synthesize ___ _____ )

A

Only the liver has the capacity to eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesize bile salts)

48
Q

where is HDL mainly formed?

A

the liver

49
Q

what is the initial form of HDL?

A

initially as ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre beta HDL)

50
Q

This pre beta HDL matures in the _____ to spherical ____ HDL as surface _____ is enzymatically converted to ____ ____ _____ that migrates to the core of the particle

A

This pre beta HDL matures in the plasma to spherical alpha HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle i.e. as the maturation from beta to alpha occurs the surface cholesterol becomes esterified and moves to the core.

51
Q

what does the migration of cholesterol of the HDL surface mean?

A

that there are free sites of the shell which can accept cholesterol - it can do this from peripheral sites in the body.

52
Q

Mature HDL accepts excess cholesterol from the p____ ______ of cells (e.g. ______) and delivers cholesterol to the ____ , known as reverse cholesterol transport, by several mechanisms

A

Mature HDL accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver, known as reverse cholesterol transport, by several mechanisms

53
Q

there are several mechanisms of reverse cholesterol transport,
1- HDL reaching the liver interacts with a receptor (_________________) that allows the transfer of cholesterol and cholesteryl esters into the hepatocytes - this is a direct pathway

  1. or in the plasma, ____________(CETP) mediates the transfer of cholesteryl esters from ____ to ____ and ____, indirectly returning cholesterol to the liver.
A

scavenger receptor beta 1, SR- B1

  1. or in the plasma, cholesterol ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver.
54
Q

what is the main action of statins

A

They are very effective in reducing total and LDL cholesterol (up to 60%), decrease triglycerides (up to 40%) and modestly increase HDL (about 10%)

55
Q

what are two examples of statins?

A

examples are simvastatin and atorvastatin

56
Q

how do statins work?

A

they act as competative inhibitors of HMG-CoA reductase - this is responsible for cholesterol synthesis

57
Q

statins block the conversion of HMG-CoA to _______

A

HMG-CoA to mevalonate

58
Q

Decrease in the hepatocyte cholesterol synthesis causes a compensatory increase in ____ _____ ____ and enhanced clearance of _____

A

Decrease in the hepatocyte cholesterol synthesis causes a compensatory increase in LDL receptor expression and enhanced clearance of LDL.

59
Q

Statins are INEFFECTIVE in ______ _______ ______ where ____ receptors are lacking

A

Statins are INEFFECTIVE in homoxygous familial hypercholesterolaemia where LDL receptors are lacking

60
Q

what are the other beneficial effetcs of statins? 4

A
  1. decreased inflammation
  2. reversal of endothelial dysfunction
  3. decreased thrombosis
  4. stabilisation of atherosclerotic plaques
61
Q

what are the side effects of statins?

A

myositis and rarely rhabdomylosis

62
Q

who should statins not be prescribed to?

A

pregnant women

63
Q

what is the action of fibrates?

A

Causes a pronounced decrease in triglycerides (up to 50%) and modest decrease (up to 15%) in LDL and increase (up to 20%) in HDL

64
Q

how do fibrates work?

A

They act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of several genes (for lipoprotein lipase on endothelial cells), including that encoding LPL so helps to remove triglycerides from theaprtciles

65
Q

combination of fibrates with ____ is not recommended - they have similar side effects?

A

statins

66
Q

They are best avoided in alcoholics who are predisposed to _________, but also best avoided in _____

A

They are best avoided in alcoholics who are predisposed to hypertriglyceridaemias, but also rhabdomyolosis

67
Q

Bile acid binding resins cause the excretion of ___ ____ resulting in more ______ to be converted to____ _____ by interrupting enterohepatic recycling

A

Bile acid binding resins cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling

68
Q

giev three examples of drugs that inhibit cholesterol absorption

A

colestyramine, colestipol, colsevelam

and ezetimibe

69
Q

Binding resins do 2 things, what are they?

A

i) decrease the absorption of triglycerides
ii) increase LDL receptor expression - this is because the increased secretion of bile salts and cholesterol causes the liver to compensate by expressing more LDL receptors so you get increased clearance from plasma

70
Q

how does ezetimibe work?

A

acts to inhibit the NPC1L1 transport protein which is present in enterocytes of the duodenum. This reduces the absorption of cholesterol

71
Q

ezetimibe is used in combination with _____ when the latter alone does not achieve a sufficient response

A

It is used in combination with statins when the latter alone does not achieve a sufficient response

72
Q

what are the side effects of ezetimibe?

A

diarrhoea

abdominal pain and headache may occur

73
Q

who is ezetimibe ot indicated for?

A

breast feeding females

Cardiovascular: pharmacology (6 decks)

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