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Cardiovascular 2018 > Lipid metabolism and cardiovascular disease > Flashcards

Lipid metabolism and cardiovascular disease Flashcards

1
Q

How soluble are lipids?

A

Insoluble (sparingly soluble in water)

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2
Q

What are lipids essential for?

A

membrane biogenesis and membrane integrity

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3
Q

what are lipids used as?

A

energy sources, precursors for hormones and signalling molecules

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4
Q

How are non-polar lipids transported in the blood?

A

(cholesterol esters & triglycerides) are transported in the blood within lipoproteins (e.g. HDL, LDL)

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5
Q

What is cardiovascular disease (atherosclerosis) strongly associated with?

A
  • elevated LDL

- decreased HDL

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6
Q

What are the causes of cardiovascular disease?

A

Diet and lifestyle

Genetic (familial hypercholesterolaemia)

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7
Q

What is the structure of lipoproteins?

A

microscopic and spherical

hydrophobic core= esterified cholesterol and triglycerides

hydrophilic coat= monolayer of amphipathic cholesterol, phospholipids and one or more apoproteins

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8
Q

What are the major lipoproteins?

A
  • HDL (apoA1, apoA2)
  • LDL (apoB-100)
  • VLDL (apoB-100)
  • chylomicrons (apoB-48)
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9
Q

What do ApoB-lipoproteins do?

A

deliver triclycerides;

  1. to muscle for ATP biogenesis
  2. adipocytes for storage
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10
Q

Where are chylomicrons formed and what do they do?

A

chylomicrons are formed in intestinal cells, transport dietary triglycerides- exogenous pathway

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11
Q

What is the life cycle of ApoB-containing liposomes?

A
  1. assembly (with apoB100 in the liver and apoB48 (a truncated variant) in the intestine)
  2. intravascular metabolism (involving hydrolysis of the triglyceride core)
  3. receptor mediated clearance
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12
Q

How are triglycerides formed?

A
  • formed from monoglyceride and free fatty acid long chain from digestion of dietary fat
  • they undergo triglyceride synthesis in the enterocyte
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13
Q

How are cholesteryl esters formed?

A
  • niemann-pick C1 like 1 protein (NPC1L1) transports cholesterol (from digestion of dietary fat and bile) acrss the gut lumen into the enterocyte
  • undergoes esterification
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14
Q

What is the first stage in the formation of chylomicrons?

A

the triglyceride enters the endoplasmic reticulum of the enterocyte where a ribosome synthesised apoB

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15
Q

What is the second stage in the formation of chylomicrons?

A

triclyceride undergoes lipidation by MTP Microsomal triglyceride transfer protein

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16
Q

What is the third stage in the formation of chylomicrons?

A

cholesterol ester is added to the group and it becomes a chylomicron

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17
Q

What is the fourth stage in the formation of chylomicrons?

A

-chylomicrons exit the enterocyte by exocytosis after the formation of a second apoprotein apoA1, enters lymphatics and is carried in lymph to the systemic circulation via the thoracic duct

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18
Q

Where are VLDL containing triglycerides assembled?

A

liver hepatocytes from free fatty acids derived from

  1. adipose tissue (particularly during fasting)
  2. de novo synthesis

-MTP lipidated apoB100 forming nascent VLDL that coalesces with triglyceride droplets

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19
Q

How are triglyceride molecules delivered to adipose and muscle tissue?

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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20
Q

Where are LPL enzymes found?

A

associated with the endothelium of capillaries in adipose and muscle tissue

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21
Q

What des ApoCII facilitate?

A

binding of chylomicrons and VLDL particles to LPL

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22
Q

What does LPL do?

A

hydrolyses core tryclycerides to free fatty acids and glycerol which enter tissues

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23
Q

What are particles depleted of triglycerides but still containing cholesteryl esters termed ?

A

chylomicron and VLDL remnants

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24
Q

What happens to the cholesterol remnants?

A

further metabolised by hepatic lipase

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25
Q

What happens to apoB48-containing remnants ?

A

They are all cleared by receptor-mediated endocytosis into hepatocytes

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26
Q

What happens to apo100 containing remnants?

A

50% are cleared by receptor-mediated endocytosis into hepatocytes

27
Q

What happens to apo100 remnants that are not cleared by receptor-mediated endocytosis into hepatocytes?

A

they lose further triglyceride through hepatic lipase, become smaller and enriched in cholersteryl ester and via intermediate density lipoproteins become LDL particles lacking poE and retaining solely apoB100

28
Q

What is clearance of LDL particles dependent upon?

A

-dependent upon the LDL receptor expressed by the liver and other tissues.

Clearance by liver is most important

29
Q

How does cellular uptake of LDL particles occur?

A

Via receptor mediated endocytosis

30
Q

What is released in the cell lysosome in clearance of LDL?

A

-within the cell at the lysosome, cholesterol (c) is released from cholesterol ester (CE) by hydrolysis

31
Q

What does released cholesterol in the lysosome cause?

A
  • inhibition of HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
  • down regulation of LDL receptor expression
  • storage of cholesterol as cholesterol ester
32
Q

Why is LDL bad cholesterol?

A

low density lipoprotein (LDL) from the blood into the intima of the artery. LDL subsequently oxidized to atherogenic oxidised LDL (OXLDL)

33
Q

What is the process of atherogenesis after oxidation to OXLDL?

A
  1. Migration of monocytes (white blood cell) across the endothelium into the intima where they become macrophages
  2. 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)
  3. Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
  4. 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)
34
Q

Why is HDL the good cholesterol?

A

-HDL = remove excess cholesterol from cells = transporting it in plasma to the liver. Only the liver can eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesize bile salts)

35
Q

Where is HDL formed?

A

HDL is formed mainly in the liver, initially as ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre-b-HDL)

36
Q

What happens to pre-b-HDL?

A
  • Disc-like pre-b-HDL matures in plasma to spherical -HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
37
Q

What does mature HDL do?

A

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

38
Q

What are the mechanisms by which mature HDL accepts cholesterol?

A
  • HDL reaching the liver interacts with a receptor (scavenger receptor-B1, SR-B1) that allows transfer of cholesterol and cholesteryl esters into hepatocytes
  • 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
39
Q

What are the drugs of choice to reduce LDL?

A

Statins

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

40
Q

Give some examples of statins?

A

Examples are simvastatin and atorvastatin

41
Q

How do statins work?

A

inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - rate limiting step in cholesterol synthesis in hepatocytes

42
Q

What does a decrease in hepatocyte cholesterol synthesis cause?

A

a compensatory increase in LDL receptor expression and enhanced clearance of LDL

43
Q

When are stating ineffective?

A

statins are ineffective in homozygous familial hypercholesterolaemia where LDL receptors are lacking

44
Q

What are some other benefits of statins?

A
  • Decreased inflammation
  • Reversal of endothelial dysfunction
  • Decreased thrombosis
  • Stabilization of atherosclerotic plaques
45
Q

When are statins administered?

A

Administered orally at night

46
Q

What are the adverse effects of statins?

A

myositis and rarely rhabdomyolosis incidence of which is increased if statin is combined with a fibrate

47
Q

What are the effects of fibrates?

A

Cause a pronounced decrease in triglycerides (up to 50%) and modest decreases (up to 15%) and increases (up to 20%) in LDL and HDL, respectively

48
Q

Give two examples of fibrates

A

bezafibrate and gemfibrozil

49
Q

What are the first line drugs in in patients with very high triglyceride levels?

A

fibrates

50
Q

How do fibrates work?

A

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

51
Q

What are the side effects of fibrates?

A

statins may rarely cause myositis - combination with latter is generally inadvisable.

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

Incidence of other adverse effects (G.I. symptoms, pruritus and rash) greater than for statins

52
Q

What kind of drugs inhibit cholesterol absorption?

A

Bile acid binding resins

53
Q

How do Bile acid binding resins work?

A

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

54
Q

What are some examples of Bile acid binding resins?

A

colestyramine, colestipol, colsevelam

55
Q

How are bile acid binding resins administered?

A

Ingested orally, not absorbed from the G.I. tract, prevent the reabsorption of bile salts (which is normally virtually all)

56
Q

What do bile acid binding resins cause?

A

(i) decreased absorption of triglycerides

(ii) increased LDL receptor expression

57
Q

What are the side effects of bile acid binding resins?

A

G.I. tract irritation

58
Q

How does ezetimbe work?

A

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

59
Q

What does ezetimbe cause?

A

Causes a decrease in LDL (about 18%) with little change in HDL

60
Q

How is ezetimbe administered?

A

Administered orally

Used in combination with statins when the latter alone does not achieve a sufficient response

61
Q

How is ezetimbe metabolised?

A

Metabolised to an active metabolite that undergoes enterohepatic recycling that contributes to a long half-life of approximately 22 hours

62
Q

What are the side effects of ezetimbe?

A

diarrhoea, abdominal pain and headache may occur

63
Q

when is ezetimbe contraindicated?

A

breast feeding females

Cardiovascular 2018 (39 decks)

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