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Cardiovascular (Annie) > Cholesterol & Lipid Metabolism > Flashcards

Cholesterol & Lipid Metabolism Flashcards

1
Q

Are lipids soluble in water?

A

= insoluble / sparingly soluble

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2
Q

what are lipids essential for? (3)

A

1) membrane biogenesis & membrane integrity
2) energy sources
3) precursors for hormones & signalling molecules

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3
Q

give 2 examples of non-polar lipids?

A

1) cholesterol esters

2) triglycerides

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4
Q

how are non-polar lipids transported?

A

in blood within lipoproteins

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5
Q

what are the 2 types of lipoproteins?

A

1) high density lipoproteins, HDL

2) low density lipoproteins, LDL

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6
Q

what is cardiovascular diseases, like atherosclerosis, strongly associated with? (in relation to HDL & LDL)

A

1) elevated LDL / particles rise in triglycerides

2) decreased HDL

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7
Q

what 2 causes of cardiovascular diseases?

A

1) diet
2) lifestyle
3) genetic factors
(e. g. familial hyper-cholesterolaemia)

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8
Q

what are lipoproteins?

A

= microscopic spherical particles

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9
Q

what do lipoproteins consist of?

A

1) hydrophobic core

2) hydrophilic coat

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10
Q

what does the hydrophobic core of lipoproteins contain?

A

eateries cholesterol & triglycerides

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11
Q

what does the hydrophilic coat of lipoproteins comprise?

A

= monolayer of;

1) amphipathic cholesterol
2) phospholipids
3) 1 or more apoproteins (apo)

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12
Q

what are the 4 major lipoproteins?

- what size are each of them?

A

1) HDL particles
- diameter 7-20nM

2) LDL particles
- diameter 20-30nM

3) very low density lipoproteins (VLDL) particles
- diameter 3-80nM

4) chylomicrons
- diameter 100-1000nM

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13
Q

what do HDL & LDL particles contain?

A

HDL
= apoA1 & apoA2

LDL
= apoB-100

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14
Q

what do VLDL & chylomicrons contain?

A

VLDL
= apoB-100

chylomicrons
= apoB-48

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15
Q

where do Apo-B containing lipoproteins deliver triglycerides to?

A

Deliver to;

1) muscle for ATP biogenesis
2) adipocytes for storage

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16
Q

where are chylomicrons formed and what do they do?

A

= formed in intestinal cells

= transport dietary triglycerides in the exogenous pathway

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17
Q

where are VLDL particles formed and what do they do?

A

= formed in liver cells

= transport triglycerides synthesised in that organ in the endogenous pathway

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18
Q

how do chylomicrons & VDLD differ in terms of their function?

A

Chylomicrons;
= transport dietary triglycerides the EXOGENOUS pathway

VLDL;
= transport triglycerides synthesised in the organ the ENDOGENOUS pathway

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19
Q

what are the 3 phases of the life-cycle of Apo-B containing liposomes?
- what happens in each?

A

1) assembly
= apoB100 in liver & apoB48 (a truncated variant) in the intestine

2) intra-vascular metabolism
= involves hydrolysis of triglyceride core

3) receptor mediated clearance

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20
Q

Where are VLDL particles containing triglycerides assembled and what are they assembled from?

A

= assembled in liver hepatocytes

= from free fatty acids derived from;

i) adipose tissue
ii) de novo synthesis

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21
Q

how are chylomicrons and VLDL activated?

A

activated by transfer of apoCII from HDL particles

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22
Q

what does the activation of chylomicrons and VLDL allow?

A

targets triglyceride delivery to adipose and muscle tissue

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23
Q

what is lipoprotein lipase (LPL)?

A

lipolytic enzyme associated with endothelium of capillaries in adipose & muscle tissue

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24
Q

what does ApoCII facilitate?

A

allows binding of chylomicrons and VLDL particles to LPL.

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25
Q

what does LPL do?

A

once VLDL and chylomicrons have bound to LPL, it hydrolyses core triglycerides to free fatty acids & glycerol which enter tissues.

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26
Q

what are particles depleted for triglycerides (but still containing cholesterol esters) termed?

A

termed chylomicron and VLDL remnants

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27
Q

describe the steps involved in the clearance of ApoB-containing lipoproteins?

A

1) LPL causes chylomicrons atond VLDL particles to become relatively enriched in cholesterol due triglyceride metabolism
2) Chylomicrons and VLDL dissociate from LPL
3) ApoCII is transferred to HDL particles in exchange for apoE which is a high affinity ligand for receptor mediated clearance. Particles are now remnants
4) Remnants return to the liver and are further metabolised by hepatic lipase
5) All apoB48-containing remnants and endocytosis50% of apo100 containing-remnants are cleared by receptor-mediated endocytosis into hepatocytes
6) Remaining apoB100-containing remnants loose further triglyceride through hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (IDL) become LDL particles lacking apoE and retaining solely apoB100

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28
Q

what is clearance of LDL particles dependent on?

A

dependent upon the LDL receptor expressed by the liver & other tissues

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29
Q

clearance by which organ is most important?

A

by the liver

30
Q

cellular uptake of LDL particles occurs via what?

A

via receptor-mediated endocytosis

31
Q

within the cell at the lysosome, what is cholesterol released from and what by?

A

Released from = cholesteryl ester

Released by = hydrolyses

32
Q

what 3 things does released cholesterol cause?

A

1) inhibition of HMG-CoaA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
2) down regulation of LDL receptor expression
3) storage of cholesterol as cholesterol ester

33
Q

where is atherosclerosis mainly found?

A

the focal disease of large & medium sized arteries

34
Q

how is atherosclerosis initiated by?

A

by dysfunction & injury of lining (endothelium) of blood vessels

Risk factors;

  • diabetes
  • high BP
  • smoking
35
Q

what are the 5 steps involved in disease progression?

A
  1. Uptake of low density lipoprotein (LDL) from the blood into the intima of the artery. LDL subsequently oxidized to atherogenic oxidised LDL (OXLDL)
  2. Migration of monocytes (white blood cell) across the endothelium into the intima where they become macrophages
  3. Uptake of OXLDL by macrophages (using scavenger receptors) converts them to cholesterol-laden foam cells that form a fatty streak (an early event in atherogenesis)
  4. Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
  5. The formation of an atheromatous plaque consisting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
36
Q

Yes or No.

in summary, is LDL the bad cholesterol?

A

Yes. LDL is the bad cholesterol

37
Q

Yes or No.

is HDL the good cholesterol?

A

Yes. HDL is the good cholesterol

38
Q

what role does HDL have?

A

removes excess cholesterol from cells by transporting it in plasma to liver

39
Q

what organ only has the capacity to eliminate cholesterol from the body?

A

liver has the capacity to remove it.

40
Q

where is HDL formed and how?

A

in liver, initially as ApoA1 in associated with small amount of surface phospholipid & unsterified cholesterol

41
Q

describe the maturation of disc like pre-beta-HDL?

A
  • matures in the plasma to spherical alpha-HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to core of the particle
42
Q

what is matures HDL role with cholesterol?

A

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

43
Q

what 2 mechanisms deliver cholesterol two tthe liver?

A

1) HDL reaching liver interacts with a receptor allowing transfer of cholesterol & cholesteryl esters into hepatocytes
2) in the plasma, cholesterol ester transfer protein (CETP) mediates transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver

44
Q

how does primary dyslipidaemia occur?

A

thorough combination of diet & genetic factors

45
Q

how does secondary dyslipidaemia occur?

A

consequence of other diseases (type II diabetes, hypothyrdoisism, alcoholism, liver disease)

46
Q

what class of drugs are used for lowering lipids and what do they reduce and increase?

A

statins;

  • reduce total & LDL cholesterol
  • decrease triglycerides
  • increase HDL
47
Q

what are 2 examples of stain drugs?

A

1) simvastatin

2) atorvastatin

48
Q

how do statins work?

A

competitive inhibitors of 3-hydroxy-3-methylglutaryl Coe-enzyme A (HMG-CoA)
- rate limiting step in cholesterol synthesis inn hepatocytes

49
Q

what does a decrease in hepatocyte cholesterol synthesis cause?

A

causes a compensatory increase in LDL receptor expression & enhanced clearance of LDL

50
Q

what are 4 other benefits of statins?

A

1) decreased inflammation
2) reversal of endothelial dysfunction
3) decreased thrombosis
4) stabilisation of atherlosclerotic plaques

51
Q

how are statins administered?

A

orally at night

52
Q

what are possible adverse effects of stains?

A
  • myositis

- rhabdomyolysis incidence of which is increased if stain is combined with a fibre

53
Q

what is another lipid lowering drug that could be used?

A

fibrates

54
Q

what do fibrates do?

A

cause a pronounced decrease in triglycerides & modest decrease & increase in LDL and HDL

55
Q

what are 2 examples of fibrates?

A

1) bezafibrate

2) gemfibrozil

56
Q

when are fibrates the first line drug?

A

in people with very high triglyceride levels

57
Q

how do fibrates act?

A

act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of several genes. including that encoding LPL

58
Q

describe fibrates adverse effects?

A

= few adverse effects

  • rarely cause myositis – combination with latter is generally inadvisable.
  • Best avoided in alcoholics who are predisposed to hypertriglyceridaemias, but also rhabdomyolosis
59
Q

do fibrates or statins have a higher incidence of adverse effects?

A

fibrates cause a high incidence

60
Q

name 3 drugs that inhibit cholesterol absorption?

A

1) colestyramine
2) colestipol
3) colsevelam

= they are bile acid binding resins

61
Q

what do these drugs do?

A

cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling.

62
Q

how should they be administered?

A

orally

- not absorbed from GI tract & prevents re-absoprtion of bile salts

63
Q

what 2 things do binding resins cause?

A

1) decreased absorption of triglycerides

2) increased LDL receptor expression

64
Q

what effect do they have on GI tract?

A

cause GI tract irritation

65
Q

name another drug that is used to inhibit cholesterol absorption?

A

= ezetimibe

66
Q

how does Ezetimibe work?

A
  • acts to inhibit Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol
67
Q

what effects does Ezetimibe have on LDL & HDL?

A

decreases LDL with little change in HDL

68
Q

how should Ezetimibe be taken?

A
  • in combination with statins when the latter alone does not achieve a sufficientt response
  • orally, Metabolised to an active metabolite that undergoes enterohepatic recycling that contributes to a long half-life of approximately 22 hours
69
Q

describe what adverse effects Ezetimibe may have?

A
  • diarrhoea
  • abdominal pain
  • headache
70
Q

when should Ezetimibe not be taken?

A

in breast feeding females

71
Q

Slide 6

A

Slide 6

72
Q

how are chylomicrons formed?

A

1) cholesterol
2) undergo esterification by Neumann-Pick C1-like 1 protein (NPC1L1)
3) forming cholesterol ester
this all happens in the enterocyte

in the endoplasmic reticulum;

4) apoB48 undergoes lipidattion by MTP = microsomal triglyceride transfer protein to eventually form a chylomicron
5) chylomicrons exist enterocyte by exocytosis following the addition of a second apoprotein apoA1, enters lymphatics & is carried to lymph tot systemic circulation via thoracic duct

Cardiovascular (Annie) (36 decks)

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