Cholesterol Flashcards
cholesterol is a precursor to
aldosterone
cortisol
vitamin D
sex hormones; estosterone & estradiol
structure of cholesterol
4 fused rings
branched hydrocarbon tail attached to C-17 of ring D
hydroxyl grp at C3 of A => Sterol
cell membrane cholesterol -> free -OH grp at C3 of A
plasma cholesterol -> has a FA esterified there = cholesteryl ester (even more hydrophobic)
cell membrane cholesterol vs.
plasma cholesterol
difference at C-3 of ring A
membrane - free -OH grp
plasma - FA esterified = Cholesteryl ester
specialized transport system for cholesterol?
why is this necessary?
lipoproteins
highly hydrophobic
sources of cholesterol
diet - animal products
(plants do not contain cholesterol, and sterols are poorly absorbed)
de novo synthesis - mainly in liver, intestine, adrenal cortex, and repro tissues
(accounts for 70% of cholesterol)
subcellular location of de novo cholesterol synthesis
cytoplasm and rough ER
carbon atoms for cholesterol come from
acetyl CoA
just like FA synthesis
reducing equivalents for de novo synthesis
NADPH
where does the energy driving de novo synthesis come from
hydrolysis of the high energy bonds in acetyl CoA and ATP
the first two steps of cholesterol synthesis are similar to what other synthesis? how so? whats the diff?
ketone body synthesis
condensations of 2 acetyl CoA -> acetoacetyl Co A + (3rd) acetyl CoA -> 3-hydroxy-3-methylglutaryl CoA (HMGCoA)
enz: HMGCoA synthase
Different isozymes of HMGCoA Synthase
cytosolic -> cholesterol
mito -> ketone bodies
HMGCoA Reductase
HMGCoA -> mevalonate
rate limiting, regulated step
target for statin drugs
dolichol ubiquinone (CoQ) prenylated proteins
are all made from what intermediate in cholesterol synthesis?
farnesyl PP
vitamin D is made from what intermediate in cholesterol synthesis?
7-dehydrocholesterol
regulation of cholesterol biosynthesis
Regulation of HMGCoA Reductase 3 ways: 1. transcriptional control 2. proteosomal degradation 3. covaelent modification
transcription of the HMGCoA reductase gene is controlled by the transcription factor::
SREBP-2 (sterol regulatory element binding protein-2) binds to the sterol regulatory element (SRE) of the reductase gene.
location of SREBP-2 and its associations
SREBP-2 integral to ER membrane
associated w:
SCAP (SREBP-2 cleavage activating protein)
- sterol-sensing domain
- high sterol => binds to Insig (insulin-induced gene product) = retention in the ER
when sterol levels are low…
Increase Chol Syn: SCAP no longer interacts w Insig SREBP-2/SCAP complex -> Golgi Proteases (S1P & S2P) cleave SREBP-2 = soluble amino-terminal domain that enters the nucleus and acts as a transcription factor for; HMGCoA reductase gene HMGCoA synthase LDL-R PCSK9
what about SREBP-1?
controls genes assoc w FA synthesis
reg by similar pathway
insulin (increase) glucagon (decrease)
proteosomal degradation
high sterol;
HMGCoA reductase interacts with Insig in the ER mem ->
ubiquitination and proteosomal degradation
phosphorylation / deP of HMGCoA reductase
controlled by AMPK
HMGCoA reductase:
deP = Active -> insulin dec cAMP
P’lated = Inactive -> inc glucagon
AMPK regulates what other enzyme from a diff metabolic process
Acetyl CoA carboxylase
FA synthesis
in what form is cholesterol removed? why?
bile salts
excreted as intact cholesterol in bile
fused ring -> can’t completely break down to CO2 and H2O
what are the components of bile? the use of bile?
mainly phosphatidylcholine & bile salts
surfactant to emusify fat in foods
primary bile acids, what makes them into bile salts?
cholic acid
chenodeoxycholic acid
conjugation w/ glycine or taurine => bile salts
(makes them more amphipathic)
rate-lim step in bile acid production
cholesterol-7-alpha-hydroxylase
into of -OH grp at C-7 of ring B;
cholesterol -> cholic acid
+ Cholesterol
- Cholic acid
fate of bile salts
secreted into intestine
excreted (5%) or reabsorbed (70%); enterohepatic recirculation
cholesterol is precursor to all classes of steroid hormones, name classes + examples
glucocorticoids - cortisol
mineralcorticoids - aldosterone
sex hormones - estradial, testosterone
apolipoproteins
specific proteins that are a part of plasma lipoproteins along with lipids
lipids; TG, phospholipids, chol, chol e
whats different about HDL in terms of lipoprotein classes
its the only lipoprotein class that lacks B apoproteins migrates the farthest on electrophoretic mobility
chylomicron
transport fr intestine -> periphery
TG is 98% of lipids
Apo B-48 unique to chylomicrons
- due to post-trans RNA editing of Apo B-100 in intestine -> smaller protein
Short half life (hours) should be no CMs after an overnight fast
microsomal triaclyglycerol transfer protein (MTP) role
loads apo B-48 w/ lipid in the ER, then particle is moved out into golgi and sec into lymphatic system -> blood
as nascent chylomicron
nascent vs. mature chylomicron
just apo B-48 = nascent chylomicron
+ apo E & apo C-II (both from HDL) = mature
lipoprotein lipase
mem of endothelial cells everywhere EXCEPT LIVER
recog; apo C-II
hydrolyzes TAG -> glycerol + FA
apo C-II returned to HDL
removes 90% of TAG
CM remnant cleaned up by liver (apo E receptors)
(FA -> fuel, FA-albumin, adipose
Glycerol -> lipid syn, glycolysis, gluconeogen)
accumulation of CM particles in plasma is due to a deficiency in
lipoprotein lipase or apo C-II
= hyperlipoproteinemia Type I
function of VLDL, production
transport triaclyglycerol to periphery
produced in liver
nascent = apo B-100
microsomal triglyceride transfer protein (MTP) aids in the assembly of nascent VLDL
secreted -> pickts up apo C-II & apo E from circ HDL
LDL have a higher concentration of ___ than ___ . Their main function is to carry
conc of cholesterol and cholesteryl esters > TAG, than VLDLs
carry cholesterol to peripheral tissues
Apo B-100 recog by LDL-Receptors (also recog apo E on IDLs and have a higher affinity for apo E = shorter plasma time for apo E)
LDL-Receptor binds to
LDL - apo B-100 and apo-E (IDL, higher affinity)
process of LDL-R recycling
after binding, localized to clathrin coated pits, forms endosome, proton pumps decrease the pH, causing lipoprotein to dissociate from receptor, receptor recyled to the surface
cholesterol -> ER
increases in cellular cholesterol can reduces cellular cholesterol synthesis by
- end prod inhibition of HMGCoA reductase
- inc chol -> inc proteosomal degradation of red
- transcription of LDL-R & HMG reductase genes decreased by inc chol
- enzy acyleCoA:cholesterol acyltransferase (ACAT) esterifies chol w FA for storage, inc chol -> inc ACAT activity
- serine protease PCSK9 blocks LDL-R recycling
ACAT
acylCoA:cholesterol acyltransferase (ACAT)
esterifies chol to FA for storage
inc chol increases its activity
PCKS9
a serine protease
blocks LDL-R recycling -> greater internalization of LDL -> reduced plasma LDL
familial hypercholesterolemia (FH)
genetic defect in LDL pathway
atherosclerosis -> angina, MI
genes mutated - LDL-R (most common), apo B, PCSK9
heterzygotes - serum chol 2-3x normal, MI age 30-50
tx statins
homozygotes - serum chol 4-6x normal, MI age 20-25
tx much more difficult, LDL apheresis, liver transplant
HDL
formed in blood
= lipid + apo A -1 (produced by liver and intestine)
chol released from non hepatic tissue via ABCA1 transporter (aka chol efflux regulatory protein - CERP -> tangier disease)
chol is esterified by LCAT (lecithin:cholesterol acyltransferase) which is activated by apo A-1 on the HDL => cholesterol ester
cholesteryl esters make it more spherical / mature
taken up by scavenger receptor class B type 1 (SR-B1)
what makes HDL “good”
reverse cholesterol transport - removal of chol from periphery and transport to the liver
Lipoprotein a / Lp(a)
= LDL and glycoprotein apoprotein a covalently attached to apo B-100
function unknown
high livels assoc w increased reisk of coronary heart disease
apos associated with HDL
apo A 1 (unique to HDL)
apo E
apo C
(donates apo E and apo C)
apo’s associated with LDL
ONLY apo B - 100
apo’s associated with VLDL
apo B -100
apo E
apo C
what is Cholestyramine? what does it do?
bile acid sequesterant
inc excretion of bile salts
inc synthesis of bile acids by liver
inc # of LDL-R on liver
Niacin tx
inhibits HSL
lowers Lp (a), TG, LDL-C
decreases clearance of apo A-1 from blood
-> raises HDL
moderate alcohol consumption may protect against coronary artery disease by
increasing serum conc of HDL
lipoprotein that req apo A-1
HDL
aspirin may be helpful in preventing development of atherosclerosis bc it inhibits
COX 2 -> syn of TXA2
also inhibits COX1 but effect more imp on COX2 bc the platlets that produce clotting factors are anucleated and thus can’t produce more protein
CETP
Cholesteryl ester transfer protein (CETP)
HDL exchanges cholesteryl ester for TAGs from VLDL via this enzyme
main function of VLDL
transports TG from liver to adipose and mm
main function of LDL
primary carrier of cholesterol in blood
main role of HDL
transport cholesterol from peripheral tissues to liver
ABCA-1 and SR-B1
ABCA-1 releases cholesterol from tissues
SR-B1 is the hepatic scavenger that picks up the cholesterol
HDL is the carrier
how do you calc total cholesterol?
TC = LDL-C + HDL-C + VLDL- C
with,
VLDL-C = TG / 5 (fasting)
