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Cardiovascular > Physiology and pharmacology of cholesterol and lipid metabolism > Flashcards

Physiology and pharmacology of cholesterol and lipid metabolism Flashcards

1
Q

What are lipids?

A

Insoluble or sparingly soluble in water
Essential for membrane biogenesis and membrane integrity
Energy sources, precursors for hormones and signalling molecules

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2
Q

What are examples of non-polar lipids?

A

Cholesterol esters and triglycerides

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3
Q

How are non-polar lipids transported around the body?

A

They are transported in the blood within lipoproteins (HDL and LDL)

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4
Q

What is cardiovascular disease (atherosclerosis) strongly associated with?

A 
Elevated LDL (or particles rich in triglycerides) 
Decreased HDL
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5
Q

What can cause an elevated LDL and a decreased HDL?

A 
Diet and lifestyle 
Genetic factors (familial hypercholesterolaemia)
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6
Q

What is the shape/structure of lipoproteins?

A 
They are microscopic spherical particles of 7-100 nM diameter which consist of: 
Hydrophobic core (esterified cholesterol and triglycerides) 
Hydrophilic coat (monolayer of amphipathic cholesterol, phospholipids and apoproteins)
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7
Q

What are the major lipoproteins?

A

HDL
LDL
Very-low density lipoprotein (VLDL)
Chylomicrons

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8
Q

What apoproteins are contained within HDL particles?

A

ApoA1 and ApoA2

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9
Q

What apoproteins are contained within LDL particles?

A

ApoB-100

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10
Q

What apoproteins are contained within VLDL particles?

A

ApoB-100

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11
Q

What apoproteins are contained within chylomicron particles?

A

ApoB-48

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12
Q

Where do Apo-B containtg lipoproteins deliver triglycerides to?

A

To muslce for ATP biogenesis

Adipocytes for storage

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13
Q

What is the exogenous pathway?

A

Chylomicrosn are formed in the intestinal cells and tranasport dietary triglycerides
Involves the absorption, distribution and delivery from the diet to the periphery

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14
Q

What is the endogenous pathway?

A

VLDL particles are formed in liver cells and transport triglycerides synthesised in that organ
Doesn’t directly invlove dietary lipids, involves lipids that are synthesised by the liver to the periphery

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15
Q

What is the life cycle of Apo-B-containing lipoproteins?

A

Assembly - with ApoB-100 in the liver and ApoB48 in the intestine
Intravascular metabolism - involving the hydrolysis of the triglyceride core
Receptor mediated clearance

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16
Q

What is the main site of apoB containing lipoproteins?

A

Hepatocytes and enterocytes

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17
Q

What occurs in the small intestine?

A

Fats arrive at the small intestine as lipid droplets which are digested into monoglycerides and free fatty acids
Cholesterol is also taken into the cel

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18
Q

How does cholesterol enter the cell?

A

Via Niemann-Pick-C1 like 1 proteins (NPC1L1

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19
Q

What happens to the cholesterol once it has entered the cell?

A

It is esterefied into cholesterol ester

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20
Q

How is a chylomicron made?

A

The enterocyte (in the endoplasmic reticulum) will package the monoglyceride and free fatty acid, cholesterol ester, apoB48, and apoA1 into a chylomicron via the use of MTP

21
Q

Where are the chylomicrons absorbed?

A

They are absorbed into the lymphatic system and are carried in lymph to the systemic circulation via the thoracic duc

22
Q

How will the chylomicrons enter the systemic circulation?

A

Via the thoracic duct into the subclavian vein

23
Q

How are chylomicrons and VLDL particles activated?

A

The chylomicrons and VLDL particles can only deliver triglycerides to the adipose and muscle tissues once they have recieved apoC2 from HDL particles

24
Q

How does the liver make cholesterol?

A

The liver will recieve glucose from the bloodstream. Once it has entered the cell, the glucose will undergo respiration to ultimately produce Acetyl CoA which can be converted to cholsterol via the enzyme HMG CoA reductase

25
Q

What lipoporteins can the liver make?

A

HDL

VLDL

26
Q

What apoproteins does HDL contain?

A

apoE
apoC2
apoA1

27
Q

What apoproteins does VLDL contain?

A

apoB-100

apoC2

28
Q

What aproteins does a chylomicron contain?

A

apoB48
apoC2
apoA1

29
Q

How do VLDL and chylomicrons release triglycerides into the adipose tissues and muscle cells?

A

VLDL and chylomicrons will encounter lipoprotein lipase (LPL). apoC2 allows the VLDL and chylomicrons to bind to LPL and once bound, the LPL will liberate the triglyceride into free fatty acids and glycerol which will enter the tissues.

30
Q

What are the VLDL and chylomicrons called once they have been liberated of triglycerides?

A

They are called remnants and will travel back to the liver

31
Q

Where are LPL enzymes found?

A

On the endothelium of capillaries in adipose and muscle tissue

32
Q

What is the process by which VLDL and chylomicrons return to the liver?

A

Once they have released their triglycerides to the tissues they will dissociate from LPL
AcoC2 is then retransfered back to HDL inexchange for apoE.
These remnants then return to the liver where they are futher metabolised by hepatic lipase
All apoB48 (chylomicrons) and half of the VLDL particles are cleared by receptor-mediated endocytosis into hepatocytes.
The remaining VLDL remnants lose further triglycerides through hepatic lipase and become IDL
These IDL then becomes an LDL particle that lacks apoE but retains sole,y aopB-100

33
Q

What is the clearance of LDL particles dependent on?

A

The LDL receptor expressed by the liver and other tissues. Clearance by the liver is most important

34
Q

How do cells uptake LDL?

A

Via receptor-mediated endocytosis

35
Q

How does the cholesterol get released from the core of the LDL?

A

The particle will bind to the lysosome causing the release of cholesterol ester.

36
Q

What will the empty LDL particle do?

A

It will move back towards the cell surface to pull more LDL into the cell

37
Q

What does the release of cholesterol cause?

A

The inhibition of HMG-CoA reductase which is the rate limiting enzyme in de nova cholesterol synthesis
Down regulation of LDL receptor expression
Storage of cholesterol as cholesterol ester

38
Q

What is the fates of cholesterol once it has been released from the LDL?

A

It can be stored as a cholesterol ester, some of it is used to synthesize steroid hormones and some of it is used to synthesize bile acid

39
Q

What is the action of statins?

A

They block synthesis of cholesterol in the liver cells and therefore increase the surface expression of LDL receptors, therefore LDL is more readily cleared from the plasma

40
Q

What are the risk factors for arthersclerosis?

A

Diabetes
High BP
Smoking

41
Q

What is the disease progression of atherosclerotic plaques?

A

Uptake of LDL from the blood into the intima of the artery. LDL subsequently to atherogenic oxidised LDL (OXLDL)
Migration of monocytes (white blood cell) across the endothelium into the intima where they become macrophages
Uptake of OXLDL by macrophages (using scavenger receptors) converts them to cholesterol-laden foam cells that form a fatty streak
Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen

42
Q

What is in an atheromatous plaque?

A 
Lipid core (product of dead foam cells) 
Fibrous cap (smooth muscle cells and connective tissue)
43
Q

What is reverse cholesterol transport?

A

Mature HDL accepts excess cholesterol from the plasma membrane of cells (macrophages) and delivers cholesterol to the liver. This is reverse cholesterol transport

44
Q

What causes primary dyslipideamia?

A

A combination of diet and genetic factors

45
Q

What causes secondary dyslipidaemia?

A

It is a consequence of other diseases (type 2 diabetes, hyperthyrodism, alcoholism and liver disease

46
Q

What are the benefits of statins?

A 
Reduce LDL
Decreased inflammation 
Reversal of endothelial dysfunction 
Decreased thrombosis 
Stabilization of atherosclerotic plaques
47
Q

What are the adverse effects of statins?

A

Myositis - inflammation of skeletal muscle

Rhabdomyolosis

48
Q

What is the effects of fibrates?

A

Decrease in triglycerides and LDL and an increase in HDL

They act as an agonist for a gene that is responsible for holding LPL, helping to clear triglycerides from the blood

49
Q

What are some examples of fibrates?

A

Bezafibrate

Gemfibrozil

Cardiovascular (27 decks)

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