Lectures 21-22 Cholesterol Metabolism Flashcards
Cholesterol
membrane
made in liver from acetyl-CoA
transported by large lipoproteins
used to make steroids
Eicosanoids
fatty acid derivitaives
precursors to other blood clotting molecs and stuff
NOT DERIVED FROM CHOLESTEROLS
What is cholesterol derived from
ALL from acetyl-CoA
What IS cholesterol?
a lipid
its hydrophoibic
Generation of cholesterol: major points
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
what enzyme does statin drugs target?
HMG CoA reductase
Is cholesterol metabolism hard or easy
LOTS OF STEPS
Compound… we start with a 2 carbon compound (acetyl CoA)…
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
3 fates of cholesterol
- combined with fatty acid to make cholesterol ESTER
esters can be stored or exported - Cholesterols can become bile acids (less hydrophobic!)
Bile Acids can…
Solubelilze dietary fats
reabsorbed so they can can lower cholesterol
be excreted as waste
one way to lower cholesterol levels
use bile acid resins
bile acid resisn bind to bile acids
bile acids secreted instead of reabsorbed
Explain how eating bile acid resins can deplete the body of cholesterol
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
What do bile acid RESINS do?
aid in binding up and excreting bile acids
particles that choleseterols are solublized into so they can circulate
chylomocrions
LDL
VLDLs
HDL
all have hydrophobic core
surfaces have at least one apolipoprotein
Why do we solubilize cholesterol into things like VLDLs, HDLs, etc
so that they can circulate in the blood!
chylomicrons
very few cholesterol esters (3)
lots of triacylglycerols (85)
LDL
some cholesterol esters (12) some triacylglycerols (50)
VLDL
Lots of cholesterol esters (37) little triacylglycerols (10)
HDL
More cholesterols esters (15)
VERY little triacylglycerols (4)
How do we ID good and bad cholesterols???
amount of cholesterol esters
Consider that circulating plasma cholesterol is probably bad, then is it better to have high or low levels of LDL? HDL?
LOW levles of LDL good
HIGH levels of HDL good
structure of the cholesterol lipoproteins
cholesterols inside w/ triacylglycerols
lipid bilayer
protiens on outside
Which class of lipoproteins are responsible for the gross blood plasma that appears w/in one hour of eating the triple burger
chylomicrons
Chylomicrons in circulating and disributing fatty acids…
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)
VLDLs in circulating and distributing fatty acids
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
LDLs in circulating and distributing fatty acids
can be made from left overs of VLDLs
distribute cholesterol to other tissues
this is why they’re BAD
HDLs in circulating and distributing
picks up cholesterol left in tissues (likely by LDLs)
brings found cholesterol back to liver
“cholesterol scavenger”
made in liver
How does HDL do cholesterol scavenging??
apolipoproteins on surface!
activate serum protein LCAT
LCAT pulls cholesterol out of cell membranes, esterifies it
How do we take the cholesterol out?
cell membranes made from phospholipids
LCAT takes a fatty acid tail from a phospholipid and attaches it to the cholesterols, takes this part away
Cardiovascular Diseases (CVD) due to…
cholesterol plaque buildup in arteries where walls are a little bit damaged
can block blood flow or break off and cause stroke/heart attack
LDL… how they enter cells?
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
What pathway is activated when cholesterol levels are low inside liver cells
LDL receptor protein production
nucleus says MAKE MORE
when cholesterol levels are high, what happens?
ACAT enzyme activated:
cholesterols esterified
Lipid droplets filled with cholesterol esters
How does having more LDL receptors on the cell increase the cholesterol pool?
receptors grab more LDL particles to bring into cell
Statin drugs!
inhibit cholesterol biosynth
How do statin drugs inhibit cholesterol biosynth??
block HMG-CoA reductase
bind to enzyme active site to do so because its structure is similar to HMG-CoA reductase
How do statin drugs lower serum LDL levels and thereby reduce the risk of cardiovascular disease??
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!!!
Blocking dietary cholesterol uptake. what drug?
Ezetimibe
How does Ezetimibe work?
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
What if we hit both the dietary uptake and the biosynthetic process??
LDL levlels continue to decrease, but CVD doesnt decrease
Why doesn’t combo drug work to lower rate of CVD? (it DOES decrease serum cholesterol though)
maybe LDL isn’t the only thing that causes CVD
we don’t know everything, serum choleterols isnt the only factor in CVD
Steroids: synthesized from cholesterol. Where?
brief (very) pathway?
adrenal glands (produces testosterone for women) testes ovaries
Cholesterol–>progesterone–> steroids
Steriods and gene expression
very hydrophobic, so brouth into nucleus of cell
binding which causes conf changes which controls gene expression
Steroid Agonists
activate steroid receptor signaling
can turn on OR off gene expression
Steroid Antagonists
inhibit steroid receptors signaling, turn of RECEPTOR signaling
Eicosandoids
fatty acid derivitives paracrine signalers (inside cell) short term signals Prostaglandins Thromboxanes Leukotrienes
Prostaglandins
stim inflammatory response
control secretion of mucins that protect stomach lining from low pH
Thromboxanes
regulate blood vessel constriction and platelet aggregation
Leukotrienes
pro-inflammatory molecs
associated with asthma
Eicosandoids Production
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.
COX-1
in stomach
generates prostaglandins from arachidonate to protect stomach lining
EVERYWHERE in body
COX-2
generated at inflammation sites to CONTINUE inflammatory response
to go from arachidonate to prostaglandin
Prostacyclin Synthase
prevent platelet aggregation
go from arachidonate to prostacyclin
What do aspirin and ibuprogen do?
inhibit COX 1 and COX2: Inhibit inflammatory response
Vioxx and Celebrex
inhibit COX-2, but also prostacyclin synthase a little bit
Aspirin
acetylsalicylic acid
COX-2 Inhibitors (to block inflammatory response)
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
What explains the side effect of aspirin and ibuporten in causing stomach bleeding
it inhibits production of mucins, which protect stomaching lining
What explains the side effect of Vioxx and Celebrex causing heart attacks
also inhibit prostocyclin synthase
this leads to not being able to stop platelet agregation/decrease blood clotting
you get a heart attack
