Lectures 21-22 Cholesterol Metabolism Flashcards

1
Q

Cholesterol

A

membrane
made in liver from acetyl-CoA
transported by large lipoproteins
used to make steroids

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2
Q

Eicosanoids

A

fatty acid derivitaives
precursors to other blood clotting molecs and stuff
NOT DERIVED FROM CHOLESTEROLS

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3
Q

What is cholesterol derived from

A

ALL from acetyl-CoA

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4
Q

What IS cholesterol?

A

a lipid

its hydrophoibic

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5
Q

Generation of cholesterol: major points

A

rate limiting step: enzyme HMG-CoA reductase makes HMG-CoA into mevalonate
uses two NADPHs and releases a conezyme A
carbons come from acetyl CoA
regulation happens early!
its a complicated process

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6
Q

what enzyme does statin drugs target?

A

HMG CoA reductase

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7
Q

Is cholesterol metabolism hard or easy

A

LOTS OF STEPS

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8
Q

Compound… we start with a 2 carbon compound (acetyl CoA)…

A
go to a 6 C
to a 5 C
put two together to get 10C then add 5C so we get 15C
then 2 of those makes 30C
lose a few carbons: end up with 27C
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9
Q

3 fates of cholesterol

A
  1. combined with fatty acid to make cholesterol ESTER
    esters can be stored or exported
  2. Cholesterols can become bile acids (less hydrophobic!)
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10
Q

Bile Acids can…

A

Solubelilze dietary fats
reabsorbed so they can can lower cholesterol
be excreted as waste

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11
Q

one way to lower cholesterol levels

A

use bile acid resins
bile acid resisn bind to bile acids
bile acids secreted instead of reabsorbed

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12
Q

Explain how eating bile acid resins can deplete the body of cholesterol

A

you need to make more bile acids from cholesterol
if we excrete them, more cholesterol will be used up in creating bile acids

resins bind up the bile acids to break down and excrete them

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13
Q

What do bile acid RESINS do?

A

aid in binding up and excreting bile acids

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14
Q

particles that choleseterols are solublized into so they can circulate

A

chylomocrions
LDL
VLDLs
HDL

all have hydrophobic core
surfaces have at least one apolipoprotein

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15
Q

Why do we solubilize cholesterol into things like VLDLs, HDLs, etc

A

so that they can circulate in the blood!

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16
Q

chylomicrons

A

very few cholesterol esters (3)

lots of triacylglycerols (85)

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17
Q

LDL

A
some cholesterol esters (12)
some triacylglycerols (50)
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18
Q

VLDL

A
Lots of cholesterol esters (37)
little triacylglycerols (10)
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19
Q

HDL

A

More cholesterols esters (15)

VERY little triacylglycerols (4)

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20
Q

How do we ID good and bad cholesterols???

A

amount of cholesterol esters

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21
Q

Consider that circulating plasma cholesterol is probably bad, then is it better to have high or low levels of LDL? HDL?

A

LOW levles of LDL good

HIGH levels of HDL good

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22
Q

structure of the cholesterol lipoproteins

A

cholesterols inside w/ triacylglycerols
lipid bilayer
protiens on outside

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23
Q

Which class of lipoproteins are responsible for the gross blood plasma that appears w/in one hour of eating the triple burger

A

chylomicrons

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24
Q

Chylomicrons in circulating and disributing fatty acids…

A

form in intestines
can deliver fatty acids elsewhere
lipases: removal of fatty acids carried by them
remaining praticles go back to liver to be reused (can make VLDLs)

25
Q

VLDLs in circulating and distributing fatty acids

A

can be made from left overs of chylomicrons
circulate
leave fatty acids in other tissues
remnants are IDLs, can go back to liver or make LDLs
again… BAD

26
Q

LDLs in circulating and distributing fatty acids

A

can be made from left overs of VLDLs
distribute cholesterol to other tissues
this is why they’re BAD

27
Q

HDLs in circulating and distributing

A

picks up cholesterol left in tissues (likely by LDLs)
brings found cholesterol back to liver
“cholesterol scavenger”
made in liver

28
Q

How does HDL do cholesterol scavenging??

A

apolipoproteins on surface!
activate serum protein LCAT
LCAT pulls cholesterol out of cell membranes, esterifies it

29
Q

How do we take the cholesterol out?

A

cell membranes made from phospholipids

LCAT takes a fatty acid tail from a phospholipid and attaches it to the cholesterols, takes this part away

30
Q

Cardiovascular Diseases (CVD) due to…

A

cholesterol plaque buildup in arteries where walls are a little bit damaged

can block blood flow or break off and cause stroke/heart attack

31
Q

LDL… how they enter cells?

A

LDL interacts with cell receptors, brought in as a vescile
vesciles divide, cholesterol esters and LDL brough in (in lysosome), receptors go back to surface

cholesterol esters broken down, contribute to cellular cholesterol pool

32
Q

What pathway is activated when cholesterol levels are low inside liver cells

A

LDL receptor protein production

nucleus says MAKE MORE

33
Q

when cholesterol levels are high, what happens?

A

ACAT enzyme activated:
cholesterols esterified
Lipid droplets filled with cholesterol esters

34
Q

How does having more LDL receptors on the cell increase the cholesterol pool?

A

receptors grab more LDL particles to bring into cell

35
Q

Statin drugs!

A

inhibit cholesterol biosynth

36
Q

How do statin drugs inhibit cholesterol biosynth??

A

block HMG-CoA reductase

bind to enzyme active site to do so because its structure is similar to HMG-CoA reductase

37
Q

How do statin drugs lower serum LDL levels and thereby reduce the risk of cardiovascular disease??

A

target intercellular pathway
Blocking HMG-CoA reductase=lower cholesterol pool
Then we active the LDL receptor protein production=more surface receptors
so we bring in more LDL particles from SERUM

then they won’t be deposited in arteries!!!! YAY!!!

38
Q

Blocking dietary cholesterol uptake. what drug?

A

Ezetimibe

39
Q

How does Ezetimibe work?

A

block uptake of cholesterol from diet
targets transporters from intestines from bringing cholesterols into cells

reduce LDL serum levels by 20%, inc HDL levels by 5%
WHY HDL inc???? liver says cholesterol levels are low, so HDL takes more cholesterol back to it

40
Q

What if we hit both the dietary uptake and the biosynthetic process??

A

LDL levlels continue to decrease, but CVD doesnt decrease

41
Q

Why doesn’t combo drug work to lower rate of CVD? (it DOES decrease serum cholesterol though)

A

maybe LDL isn’t the only thing that causes CVD

we don’t know everything, serum choleterols isnt the only factor in CVD

42
Q

Steroids: synthesized from cholesterol. Where?

brief (very) pathway?

A
adrenal glands (produces testosterone for women)
testes
ovaries

Cholesterol–>progesterone–> steroids

43
Q

Steriods and gene expression

A

very hydrophobic, so brouth into nucleus of cell

binding which causes conf changes which controls gene expression

44
Q

Steroid Agonists

A

activate steroid receptor signaling

can turn on OR off gene expression

45
Q

Steroid Antagonists

A

inhibit steroid receptors signaling, turn of RECEPTOR signaling

46
Q

Eicosandoids

A
fatty acid derivitives
paracrine signalers (inside cell)
short term signals 
Prostaglandins
Thromboxanes
Leukotrienes
47
Q

Prostaglandins

A

stim inflammatory response

control secretion of mucins that protect stomach lining from low pH

48
Q

Thromboxanes

A

regulate blood vessel constriction and platelet aggregation

49
Q

Leukotrienes

A

pro-inflammatory molecs

associated with asthma

50
Q

Eicosandoids Production

A

ligand binding to GCPRs activates G proteins
phospholipase A2 cleaves a tail of a membrane phospholipid, used to make eicosanoids from arachidonate by COX1 and 2, other things etc.

51
Q

COX-1

A

in stomach
generates prostaglandins from arachidonate to protect stomach lining
EVERYWHERE in body

52
Q

COX-2

A

generated at inflammation sites to CONTINUE inflammatory response
to go from arachidonate to prostaglandin

53
Q

Prostacyclin Synthase

A

prevent platelet aggregation

go from arachidonate to prostacyclin

54
Q

What do aspirin and ibuprogen do?

A

inhibit COX 1 and COX2: Inhibit inflammatory response

55
Q

Vioxx and Celebrex

A

inhibit COX-2, but also prostacyclin synthase a little bit

56
Q

Aspirin

A

acetylsalicylic acid

57
Q

COX-2 Inhibitors (to block inflammatory response)

A

Non-selective inhibitors (aspirin, Motrin): fit into enzyme active sites of COX 1 and 2
Selective: fit into enzyme active site of COX-2, inhibit prostocyclin synthase

58
Q

What explains the side effect of aspirin and ibuporten in causing stomach bleeding

A

it inhibits production of mucins, which protect stomaching lining

59
Q

What explains the side effect of Vioxx and Celebrex causing heart attacks

A

also inhibit prostocyclin synthase
this leads to not being able to stop platelet agregation/decrease blood clotting

you get a heart attack