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Biochem > Cholesterol > Flashcards

Cholesterol Flashcards

1
Q

cholesterol is a precursor to

A

aldosterone
cortisol
vitamin D
sex hormones; estosterone & estradiol

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2
Q

structure of cholesterol

A

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)

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3
Q

cell membrane cholesterol vs.

plasma cholesterol

A

difference at C-3 of ring A

membrane - free -OH grp
plasma - FA esterified = Cholesteryl ester

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4
Q

specialized transport system for cholesterol?

why is this necessary?

A

lipoproteins

highly hydrophobic

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5
Q

sources of cholesterol

A

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)

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6
Q

subcellular location of de novo cholesterol synthesis

A

cytoplasm and rough ER

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7
Q

carbon atoms for cholesterol come from

A

acetyl CoA

just like FA synthesis

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8
Q

reducing equivalents for de novo synthesis

A

NADPH

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9
Q

where does the energy driving de novo synthesis come from

A

hydrolysis of the high energy bonds in acetyl CoA and ATP

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10
Q

the first two steps of cholesterol synthesis are similar to what other synthesis? how so? whats the diff?

A

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

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11
Q

HMGCoA Reductase

A

HMGCoA -> mevalonate

rate limiting, regulated step

target for statin drugs

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12
Q 
dolichol
ubiquinone (CoQ)
prenylated proteins

are all made from what intermediate in cholesterol synthesis?

A

farnesyl PP

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13
Q

vitamin D is made from what intermediate in cholesterol synthesis?

A

7-dehydrocholesterol

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14
Q

regulation of cholesterol biosynthesis

A 
Regulation of HMGCoA Reductase
3 ways:
1. transcriptional control
2. proteosomal degradation
3. covaelent modification
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15
Q

transcription of the HMGCoA reductase gene is controlled by the transcription factor::

A

SREBP-2 (sterol regulatory element binding protein-2) binds to the sterol regulatory element (SRE) of the reductase gene.

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16
Q

location of SREBP-2 and its associations

A

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

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17
Q

when sterol levels are low…

A 
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
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18
Q

what about SREBP-1?

A

controls genes assoc w FA synthesis
reg by similar pathway
insulin (increase) glucagon (decrease)

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19
Q

proteosomal degradation

A

high sterol;
HMGCoA reductase interacts with Insig in the ER mem ->
ubiquitination and proteosomal degradation

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20
Q

phosphorylation / deP of HMGCoA reductase

A

controlled by AMPK

HMGCoA reductase:
deP = Active -> insulin dec cAMP
P’lated = Inactive -> inc glucagon

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21
Q

AMPK regulates what other enzyme from a diff metabolic process

A

Acetyl CoA carboxylase

FA synthesis

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22
Q

in what form is cholesterol removed? why?

A

bile salts
excreted as intact cholesterol in bile

fused ring -> can’t completely break down to CO2 and H2O

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23
Q

what are the components of bile? the use of bile?

A

mainly phosphatidylcholine & bile salts

surfactant to emusify fat in foods

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24
Q

primary bile acids, what makes them into bile salts?

A

cholic acid
chenodeoxycholic acid

conjugation w/ glycine or taurine => bile salts
(makes them more amphipathic)

25
Q

rate-lim step in bile acid production

A

cholesterol-7-alpha-hydroxylase

into of -OH grp at C-7 of ring B;
cholesterol -> cholic acid
+ Cholesterol
- Cholic acid

26
Q

fate of bile salts

A

secreted into intestine

excreted (5%) or reabsorbed (70%); enterohepatic recirculation

27
Q

cholesterol is precursor to all classes of steroid hormones, name classes + examples

A

glucocorticoids - cortisol
mineralcorticoids - aldosterone
sex hormones - estradial, testosterone

28
Q

apolipoproteins

A

specific proteins that are a part of plasma lipoproteins along with lipids

lipids; TG, phospholipids, chol, chol e

29
Q

whats different about HDL in terms of lipoprotein classes

A 
its the only lipoprotein class that lacks B apoproteins
migrates the farthest on electrophoretic mobility
30
Q

chylomicron

A

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

31
Q

microsomal triaclyglycerol transfer protein (MTP) role

A

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

32
Q

nascent vs. mature chylomicron

A

just apo B-48 = nascent chylomicron

+ apo E & apo C-II (both from HDL) = mature

33
Q

lipoprotein lipase

A

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)

34
Q

accumulation of CM particles in plasma is due to a deficiency in

A

lipoprotein lipase or apo C-II

= hyperlipoproteinemia Type I

35
Q

function of VLDL, production

A

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

36
Q

LDL have a higher concentration of ___ than ___ . Their main function is to carry

A

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)

37
Q

LDL-Receptor binds to

A

LDL - apo B-100 and apo-E (IDL, higher affinity)

38
Q

process of LDL-R recycling

A

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

39
Q

increases in cellular cholesterol can reduces cellular cholesterol synthesis by

A
  1. end prod inhibition of HMGCoA reductase
  2. inc chol -> inc proteosomal degradation of red
  3. transcription of LDL-R & HMG reductase genes decreased by inc chol
  4. enzy acyleCoA:cholesterol acyltransferase (ACAT) esterifies chol w FA for storage, inc chol -> inc ACAT activity
  5. serine protease PCSK9 blocks LDL-R recycling
40
Q

ACAT

A

acylCoA:cholesterol acyltransferase (ACAT)
esterifies chol to FA for storage
inc chol increases its activity

41
Q

PCKS9

A

a serine protease

blocks LDL-R recycling -> greater internalization of LDL -> reduced plasma LDL

42
Q

familial hypercholesterolemia (FH)

A

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

43
Q

HDL

A

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)

44
Q

what makes HDL “good”

A

reverse cholesterol transport - removal of chol from periphery and transport to the liver

45
Q

Lipoprotein a / Lp(a)

A

= LDL and glycoprotein apoprotein a covalently attached to apo B-100
function unknown
high livels assoc w increased reisk of coronary heart disease

46
Q

apos associated with HDL

A

apo A 1 (unique to HDL)
apo E
apo C
(donates apo E and apo C)

47
Q

apo’s associated with LDL

A

ONLY apo B - 100

48
Q

apo’s associated with VLDL

A

apo B -100
apo E
apo C

49
Q

what is Cholestyramine? what does it do?

A

bile acid sequesterant
inc excretion of bile salts
inc synthesis of bile acids by liver
inc # of LDL-R on liver

50
Q

Niacin tx

A

inhibits HSL
lowers Lp (a), TG, LDL-C
decreases clearance of apo A-1 from blood
-> raises HDL

51
Q

moderate alcohol consumption may protect against coronary artery disease by

A

increasing serum conc of HDL

52
Q

lipoprotein that req apo A-1

A

HDL

53
Q

aspirin may be helpful in preventing development of atherosclerosis bc it inhibits

A

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

54
Q

CETP

A

Cholesteryl ester transfer protein (CETP)

HDL exchanges cholesteryl ester for TAGs from VLDL via this enzyme

55
Q

main function of VLDL

A

transports TG from liver to adipose and mm

56
Q

main function of LDL

A

primary carrier of cholesterol in blood

57
Q

main role of HDL

A

transport cholesterol from peripheral tissues to liver

58
Q

ABCA-1 and SR-B1

A

ABCA-1 releases cholesterol from tissues
SR-B1 is the hepatic scavenger that picks up the cholesterol
HDL is the carrier

59
Q

how do you calc total cholesterol?

A

TC = LDL-C + HDL-C + VLDL- C
with,
VLDL-C = TG / 5 (fasting)

Biochem (13 decks)

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