Lipid Metabolism And Cardiovascular Disease

Question 1

Solubility of Lipids

Answer 1

Insoluble/ slightly soluble in water

Question 2

What are lipids essential for?

Answer 2

Membrane biogenesis and integrity

Question 3

Example of Non—polar lipids

Answer 3

Triglycerides

Cholesterol esters

Question 4

How are non-polar lipids transported?

Answer 4

In blood by lipoproteins

Question 5

HDL and LDL levels associated with atherosclerosis

Answer 5

Increased LDL or particles rich in triacylglycerols; TAGs

Decreased HDL

Question 6

Causes of CVD

Answer 6

Poor diet and exercise

Genetic factors eg familial hypercholesterolaemia

Question 7

What comprises lipoproteins

Answer 7

Hydrophobic core

Hydrophilic coat

Question 8

What comprises the hydrophobic core?

Answer 8

Esterified cholesterol

Triacylglycerols

Question 9

What comprises the hydrophilic coat?

Answer 9

Monolayer of amphipathic cholesterol, phospholipids at at least one apoproteins

Question 10

What allows lipoproteins to bind to cells?

Answer 10

Apoproteins recognised by receptors in liver

Question 11

4 classes of lipoproteins

Answer 11

HDL
LDL
VLDL
Chylomicrons

Question 12

What differentiates the classes of lipoproteins?

Answer 12

Size

Proportions of apoproteins

Question 13

Which apoproteins does HDL contain?

Answer 13

ApoA-I

ApoA-II

Question 14

Which apoproteins does LDL contain?

Answer 14

ApoB-100

Question 15

Which apoproteins does VLDL contain?

Answer 15

ApoB-100

Question 16

Which apoproteins do chylomicrons contain?

Answer 16

ApoB-48

Question 17

Role of ApoB-containing lipoproteins

Answer 17

Transport TAGs to muscle cells for biogenesis and adipocytes for storage

Question 18

Where are chylomicrons formed?

Answer 18

Intestinal cells

Question 19

What pathway do chylomicrons follow when transporting dietary triglycerides?

Answer 19

Exogenous

Question 20

Where are VLDL formed?

Answer 20

Liver cells

Question 21

What pathway do VLDLs follow when transporting TAGs made in liver?

Answer 21

Endogenous

Question 22

Life cycle of ApoB-containing liposomes

Answer 22

Assembly of ApoB-100 + 48
Intravascular metabolism- involves hydrolysis of TAG core
Receptor mediated clearance

Question 23

Assembly of chylomicrons

Answer 23

Monoglyceride and free fatty acid synthesise TAG in enterocyte
Cholesterol is esterified in the enterocyte also
These then join, along with apoB-48 in the ER to form a chylomicron
The joining is facilitated by microsomaltriglyceride transfer protein

Question 24

Assembly of VLDL particles

Answer 24

Assembled in liver hepatocytes from free fatty acids

Question 25

How are Chylomicrons and VLDL particles activated?

Answer 25

Transfer of apoC-II from HDL

Question 26

Lipoprotein Lipase

Answer 26

Lipolytic enzyme associated with endothelium of capillaries in adipose and muscle tissue

Question 27

Which apoprotein facilitates binding of chylomicrons and VLDLs to LPL?

Answer 27

ApoC-II

Question 28

Why does LPL hydrolyse core TAGs?

Answer 28

Free fatty acids and glycerol, which enter tissues

Question 29

Chylomicron and VLDL remnants

Answer 29

Particles depleted of triglycerides but still contain cholesterol esters

Question 30

What is the clearance of LDL particles dependent on?

Answer 30

LDL receptor (ApoB/E receptor) expressed by liver (and other tissues, but liver is most important)

Question 31

How does cellular uptake of LDL particles occur?

Answer 31

Via receptor mediated endocytosis

Question 32

Where is cholesterol released by cholesterol esters and by which process?

Answer 32

Within the cell at the lysosome | Hydrolysis

Question 33

What does released cholesterol do?

Answer 33

Inhibit HMG-CoA reductase Regulates LDL receptor expression Stored as CE or used as precursor for bile salt synthesis

Question 34

What does LPL cause chylomicrons and VLDL particles to do?

Answer 34

Become enriched in CE due to TAG metabolism, they then dissociate from LPL

Question 35

What happens after Chylomicrons and VLDL dissociate from LPL?

Answer 35

ApoC-II is transferred back to HDL particles in exchange for ApoE - particles are now remnants

Question 36

Where do remnants from HDL go?

Answer 36

Return to liver, where they are further metabolised by hepatic lipase

Question 37

What clears all chylomicron and half of VLDL remnants?

Answer 37

Receptor mediated endocytosis into hepatocytes

Question 38

What happens to remaining VLDL remnants?

Answer 38

They lose more TAG via hepatic lipase and become smaller and enriched in CE via IDL

Question 39

What do LDLs from IDLs lack and retain?

Answer 39

They lack apoE | They retain apoB-100

Question 40

What is apoE?

Answer 40

A high affinity ligand for receptor mediated clearance

Question 41

What is the ‘bad’ cholesterol?

Answer 41

LDL

Question 42

Why is LDL ‘bad’?

Answer 42

It is oxidised in intima of artery and uptaken by macrophages convert them to cholesterol-laden foam cells These form a fatty streak An Atheromatous plaque forms from lipid core (dead foam cells ) and fibrous cap (SM and CT)

Question 43

Role of HDL

Answer 43

Removing xs cholesterol from cells by transporting it to liver in plasma

Question 44

Why must cholesterol be transported to the liver?

Answer 44

It is the only organ which can eliminate cholesterol | - it is either secreted into bile or used to make bile salts

Question 45

Pre-Beta-DL

Answer 45

Unesterified cholesterol, small amount of surface phospholipid and apoA-I

Question 46

Where does pre-beta-HDL mature and what does it become?

Answer 46

In the plasma | Spherical alpha HDL

Question 47

Reverse cholesterol transport

Answer 47

Mature HDL accepts xs cholesterol from plasma membrane of cells and delivers it to liver

Question 48

Role of scavenger receptor-B1

Answer 48

Allows HDL to transfer cholesterol and cholesteryl esters into hepatocytes

Question 49

Which protein mediates transfer of cholesteryl esters from HDL to VLDL and LDL?

Answer 49

Cholesterol ester transfer protein

Question 50

Lipid lowering drugs

Answer 50

Statins and fibrates

Question 51

Why are statins the drug of choice when reducing LDL?

Answer 51

Reduces LDL cholesterol by up to 60% Decreases TGAs by up to 40% Increases HDL by approx 10%

Question 52

Examples of Statings

Answer 52

Simvastatin | Atorvastatin

Question 53

Which enzyme do stains competively inhibit?

Answer 53

3-hydroxy-3-methylglutaryl coA reductase | * this is the rate limiting step in cholesterol synthesis in hepatocytes

Question 54

How does decreasing hepatocytes cholesterol synthesis reduce LDL levels?

Answer 54

It causes a compensatory increase in LDL receptor expression and therefore enhances LDL clearance

Question 55

In what circumstance are LDLs ineffective? Why?

Answer 55

Homozygous familial hypercholesterolaemia | There are no LDL receptors

Question 56

Benefits of statins

Answer 56

Decreased inflammation Reversal of endothelial dysfunction Decreased thrombosis Stabilisation of atherosclerotic plaques

Question 57

Adverse effects of statins

Answer 57

``` Myositis Rhabdomyolosis (risk higher if combined with fibrate) ```

Question 58

Effect of Fibrates

Answer 58

Up to 50% decrease in TGAs Up to 15% decrease in LDL Up to 20% increase in HDL

Question 59

Examples of Fibrate

Answer 59

Bezafibrate | Gemfibrozil

Question 60

What is the first line drug used for patients with very high TGA levels?

Answer 60

Fibrates

Question 61

How do fibrates enhance the transcription of several genes?

Answer 61

They act as agonists of PPAR-alpha (nuclear recptor)

Question 62

Adverse effects of fibrates

Answer 62

Myositis Avoid combo with statins Avoid alcoholics predisposed to hypertriglyceridaemias

Question 63

Drugs that inhibit cholesterol absorption

Answer 63

Bile acid binding resins eg colestyramine, colestipol, colsevelam

Question 64

How do bile acid binding resins inhibit cholesterol absorption?

Answer 64

They cause excretion of bile salts, meaning more cholesterol can be converted to by salts by interrupting enterohepatic recycling

Question 65

Effect of bile salts on TGAs and LDLs

Answer 65

Decreases TGA absorption | Increases LDL receptor expression

Question 66

Adverse effect of bile acid binding resins

Answer 66

GI tract irritation

Question 67

How does Ezetimibe work?

Answer 67

It inhibits NPC1L1 TP in enterocytes, reducing cholesterol absorption’s

Question 68

Effect of ezetimibe on LDL

Answer 68

Decrease of about 18% in LDL levels; little change in HDL

Question 69

What must ezetimibe be used in combination with when it doesn’t achieve a sufficient response alone?

Answer 69

Statins

Question 70

Adverse effects of ezetimibe

Answer 70

Diarrhoea Abdominal pain Headaches Not to be used in breast feeding females