cholesterol and lipid transport

Question 1

what leads to atherosclerosis

Answer 1

precipitation of cholesterol and other lipids in arteries

Question 2

plaque formation pathway

Answer 2

damaged endothelial cells provide sites for accumulation of fats -> fatty streaks signal for recruitment of immune cells -> macrophages eat cholesterol and turn into foam cells in the plaque -> smooth muscle cells grow in the plaque generating fibrous cap -> plaque reduces blood flow -> necrosis at core can cause plaque rupture and thrombus formation

Question 3

what is cholesterol

Answer 3

a steroid lipid that helps to regulate cell membrane fluidity; synthesized by cells and dietry intake

Question 4

2 functions of cholesterol

Answer 4

1. precursor to steroid hormone and bile salts;
2. increases cell membrane fluidity

Question 5

why do fats need to be transported correctly though the body

Answer 5

they are highly hydrophobic and so can precipitate in blood vessels forming plaques

Question 6

what is cholesterol solubility at 30C

Answer 6

1/3million

Question 7

how are lipids transported safely around the body

Answer 7

in lipoprotein carriers -phospholipid shell with a hydrophobic lipid core (cholesterol, triglycerides)

Question 8

what part of the lipoprotein vessel dictates where the particle goes

Answer 8

the receptor targeting, hydrophilic apolipoprotein domain

Question 9

what happens to the lipid:apolipoprotein ratio as it is transported around the body

Answer 9

ratio changes throughout the body, cholesterol is always transported from low to high density lipoprotein particles

Question 10

where is the major source of cholesterol from in the body

Answer 10

the diet - eggs, fatty food, kidney, liver prawns

Question 11

role of bile salts in cholesterol digestion

Answer 11

acts as a detergent to assist in the absorption of insoluble cholesterol from the intestine

Question 12

what happens to cholesterol prior to it being packed for transport

Answer 12

it is esterefied to increase solubility
cholesterol-bile salt complex -> esterification

Question 13

what are chylomicrons

Answer 13

large triglyceride-rich lipoproteins produced in enterocytes from dietary lipids ->transport vessels

Question 14

cholesterol -> bile salt pathway (9)

Answer 14

1. chylomicrons taken up from intestine;
2. used in muscle/adipose;
3. chylomicron remnant generated, transported to liver;
4. V-LDL (very low desnity) formed in liver, transported back to muscle/adipose for use;
5. IDL (intermediate density) in blood;
6. transformed into LDL;
7. used in numerous tissues via LDL receptor;
8. picked up from tissue by HDL;
9. transported to the liver to become bile salts

Question 15

“good” vs “bad” cholesterol

Answer 15

bad - LDL, it is a measure of cholesterol headed to the tissues;
good - HDL , it is a measure of cholesterol headed to liver for excretion via bile salts

Question 16

what are the desired cholesterol levels

Answer 16

LDL - <70-130mg/dL (lower numbers are better);
HDL - >40-60mg/dL (high numbers are better);
total cholesterol <200mg/dL;
triglycerides 10-150mg/dL (low better);

Question 17

what to cholesterol therapies aim to do

Answer 17

reduce LDL levels

Question 18

what is familial hypercholesterolema

Answer 18

a genetic disease characterised by high cholesterol and LDL in blood

Question 19

familial hypercholesterolema inheritance pattern

Answer 19

autosomal dominant

Question 20

heterozygote vs homozygote phenotype for familial hypercholesterolema

Answer 20

hetero - premature CVD at age 30-40;
homo - severe childhood CVD

Question 21

familial hypercholesterolema symptoms (3)

Answer 21

1. xanthoma;
2. yellowish lipid deposits in eyelids;
3. lumpy deposits in the tendons of the hands, elbow, knees etc.

Question 22

healthy cells vs familial hypercholesterolema cells LDL uptake

Answer 22

healthy - healthy cells must have a receptor for LDL that allows it to be taken up from the plasma;
FH - the receptor must be defective causing them to have high plasma LDL;

Question 23

where is the LDL receptor gene

Answer 23

chromosome 19

Question 24

what is the familial hypercholesterolema mutation

Answer 24

single base bair mutation on C19 - tyrosine replaced with cysteine

Question 25

statins MOA (important)

Answer 25

inhibit the enzyme HMG-CoA-reductase which catalyses the rate limiting step in cholesterol synthesis -> this decreases the intracellular cholesterol conc, causing SREBPs to promote expression of LDLR (and HMG-CoA reductase) genes and thus increase uptake of LDL from the blood => blood cholesterol levels fall inhibits HMG-CoA -> mevalonic acid

Question 26

HMG-CoA negative feedback system

Answer 26

HMG-CoA-reductase gene expression is inhibited by the product of its activity i.e. cholesterol

Question 27

what is the SREBP pathway

Answer 27

sterol regulatory element binding proteins (SREBP) are transcription factors that bind to the sterol regularoty element (SRE) and promote gene expression for HMG-CoA-reductase

Question 28

how does cholesterol regulate SREBP

Answer 28

high intracellular cholesterol keeps SREBP in the cytoplasm (thus downregulate expression of the gene) -> when cholesterol is low, SREBP mover to the nucleus to stimulate expression

Question 29

what genes does SREBP switch on when in the nucleus (2)

Answer 29

HMG-CoA-reductase; LDL receptor

Question 30

where in the body is cholesterol not damaging

Answer 30

when it is in the cells

Question 31

when might statins be ineffective at reducing blood cholesterol levels

Answer 31

if dietry intake is excessive - cells may become saturated

Question 32

a mutation in what intestinal receptor can increase uptake of cholesterol from the diet

Answer 32

Neimann-Pick C1-like 1 (NPC1L1)

Question 33

how does benecol (and other plant steroids) work

Answer 33

competitively competes with cholesterol for transporter binding

Question 34

what is ezetimibe

Answer 34

a drug which acts to block NPC1L1 -> may be given along side statins in cholesterol management

Question 35

what mutation do pts with tangier disease have and what does this mean

Answer 35

ABCA1 (extrudes cholesterole from cells allowing it to become HDL) -> cannot make HDL and so have high LDL levels in the blood

Question 36

why might PCSK9 protein be targeted in cholesterol treatment

Answer 36

PCSK9 binds to LDLRs and degrades them => reduction in these will result in an increase in LDLRs