Cholesterol Metabolism Flashcards
1
Q
cholesterol synthesis pathway
A
acetyl coA -> mevalonate -> 3-isopentyl pyrophosphate -> cholesterol
2
Q
how is cholesterol transported?
A
by VLDL, LDL, HDL
3
Q
what is associated with reduced adverse CV events in middle age people?
A
reduced LDL and elevated HDL
4
Q
what inhibits cholesterol synthesis?
A
cholesterol - feedback inhibition
5
Q
what is cholesterol used to make?
A
vitamin D, bile salts, steroid hormones
6
Q
what enzyme turns acetyl coA into mevalonate?
A
HMG-coA reductase
7
Q
what happens to cholesterol levels as you age?
A
tend to increase w/ age, then stabilize around 60
8
Q
cholesterol structure
A
- 27 carbons all from acetyl coA
- 4 rings
- OH on C-3
- C-7 important in synthesis of bile acids
9
Q
cholesterol synthesis requires large amounts of what reducing equivalents?
A
NADPH
10
Q
what are the two types of HMG-coA synthase?
A
mitochondrial (ketone bodies) and cytoplasmic (cholesterol)
11
Q
HMG coA synthesis
A
acetyl coA -> acetoacetyl coA -> HMG-coA
12
Q
rate limiting step in cholesterol synthesis
A
3-hydroxy-3-methylglutaryl-coA -> mevalonate
-done by HMG-coA reductase, uses 2 NADPH
13
Q
statins
A
competitive inhibitors of HMG-coA reductase - lower plasma cholesterol levels
14
Q
what are potential side effects of statins?
A
myopathy and rhabdomyolysis
15
Q
what are the enzymes for the three reactions converting mevalonate into isopentenyl pyrophosphate?
A
- mevalonate 5’ phosphokinase
- phosphomevalonate kinase
- pyrophosphomevalonate decarboxylase
16
Q
what two substances is isopentenyl pyropyrophosphate used to make?
A
cholesterol and ubiquinone (coQ)
17
Q
polymerization of isopentenyl-PP
A
isopentenyl-PP + dimethylallyl-PP (C5 isoprenes) -> geranyl-PP (C10 polyisoprene) -> farnesyl-PP (C15 polyisoprene) -> squalene (C30 polyisoprene)
18
Q
where might you find geranyl-PP and farnesyl-PP?
A
may see as oncogenes attached to membranes
19
Q
cyclization and isomerization
A
squalene -> squalene epoxide -> lanosterol -> (19 steps) -> cholesterol
20
Q
regulation of HMG-coA reductase
A
- phosphorylated = inactive (glucagon)
- dephosphorylated = active (insulin)
- high levels of cholesterol -> proteolysis
- transcription by SREBP (sterol reg. element binding proteins)
21
Q
what are the major sites for cholesterol synthesis?
A
liver and intestine
22
Q
SCAP
A
SREBP cleavage-activating protein
- binds cholesterol and other sterols
- moves to golgi in absence of cholesterol binding
23
Q
regulation of HMG-coA reductase at the gene level
A
- sterol binding prevents transport to golgi
- proteolysis occurs in golgi - releases SREBP and DBD
- transcription of reductase gene in nucleus
24
Q
where are bile acids synthesized?
A
liver
25
rate-limiting step of bile synthesis
CYP7A1 places OH on C7 (O2 and NADPH)
26
what makes bile acid amphipathic?
carboxyl group on side chain of steroid ring
27
how are bile acids converted to salts?
Add Gly or taurine (amide bond)
28
how much bile does a typical adult liver produce daily?
0.5 - 1 L
29
what is CYP7A1 inhibited by?
bile salts
30
what do bacteria do to bile salts?
deconjugate them, remove 7-OH to produce secondary bile salts
31
bile composition
- water
- cholesterol
- bile salts
- bilirubin
32
what is cholesterol solubilized by?
phospholipids, bile salts
33
what is the composition of 80% of US gallstones?
cholesterol stones
34
factors for cholesterol gallstones
1. bile acid levels
2. biliary cholesterol secretion
3. gallbladder hypomotility
35
how are cholesterol esters transported in blood?
as FA esters
36
LCAT
lecithin: cholesterol acyltransferase
- in blood
- esterifies HDL cholesterol, so it is retained in particles
37
what is lecithin?
a phosphatidylcholine
38
ACAT
acyl: cholesterol acyltransferase
- intracellular
- packages cholesterol for VLDL and storage in liver for bild production
39
CETP
cholesterol ester transfer protein
| -HDL to VLDL transfer of cholesterol
40
what do chylomicrons transport?
dietary TGs
41
where are chylomicrons synthesized?
epithelial cells of intestine
42
chylomicrons compared to other plasma lipoprotein particles
- least dense
| - highest TGs
43
what two apolipoproteins are associated with chylomicrons?
ApoB-48 and ApoC-II and ApoE
44
what happens when chylomicrons are depleted of TGs?
ApoE is exposed and binds to receptors on liver - cholesterol is released
45
what do VLDLs transport?
endogenous TGs
46
VLDL production
excess FA from carbohydrates that are not needed for fuel are converted into TGs in the liver and packaged w/ apolipoproteins and into VLDL particles
47
is there any cholesterol in VLDLs?
yes - some cholesterol and cholesterol esters
48
apolipoproteins associated w/ VLDLs?
ApoB-100, ApoC-II, ApoE
49
fate of VLDLs
50%: remnants removed via ApoE receptor mediated endocytosis in liver
50%: VLDL -> IDL -> LDL
50
what does LDL transport?
cholesterol transport to extrahepatic tissues
51
is there any cholesterol in LDLs?
yes - rich in cholesterol and cholesterol esters
52
apolipoproteins associated w/ LDLs?
ApoB-100
53
which is the bad cholesterol: HDLs or LDLs?
LDLs
54
what do HDLs transport?
reverse cholesterol transport (tissues to liver)
55
where are HDLs formed?
liver or small intestine
56
is there any cholesterol in HDLs?
nascent has very little cholesterol
57
apolipoproteins associated with HDLs?
ApoA-1, ApoC-II, ApoE
58
what does ApoA-1 activate?
LCAT
59
what does LCAT generate cholesterol esters from?
cholesterol and phosphatidylcholine
60
what do HDL particles bind to unload cholesterol to liver (how are HDLs cleared)?
scavenger receptor-B1
61
what does LDL receptor recognize?
apoE and apoB-100
62
what does LDL receptor bind?
VLDL, LDL, IDL, chylomicron remnants
63
what does LDL receptor deficiency cause?
high blood cholesterol
64
LRP
LDL receptor related protein
65
where is LRP found?
liver, brain, placenta
66
what does LRP bind?
apoE - clears remnants?
67
LRP expression regulation
- independent of [cholesterol]
| - increases in response to insulin
68
what does SR-B1 bind?
HDL
69
what does SR-A1 or SR-A2 bind?
oxidized LDL (superoxide)
70
where are SR-A1 and -A2 found?
on macrophages
71
scavenger receptor expression regulation
-independent of [cholesterol]
72
foam cells
macrophage engorged with lipid
73
how does HDL accept cholesterol from peripheral tissue?
via ABC A1
74
how does HDL retain cholesterol?
esterification by LCAT
75
what results from inhibiting CETP?
raises HDL
76
familial hypercholesterolemia (FH) cause
defective LDL receptor:
heterozygotes - 200-400 mg/dL serum cholesterol
homozygotes - 500-800 mg/dL serum cholesterol
77
xanthomas
deposition of cholesterol rich material on tendons
| -in het adults and homo children
78
corneal arcus
white line on edge of cornea - in homo children
79
FH symptoms
- high incidence of coronary artery disease
- xanthomas
- corneal arcus
80
familial ligand defective apoB-100 (FLDB)
- similar symptoms to FH, but not as severe
- apoE also recognizes LDL receptor, so VLDL and IDL uptake is normal
- homo FLDB has similar symptoms to het FH
81
effect of cholesterol uptake on cholesterol regulation
- increased cholesterol down regulates LDL receptor (transcription)
- low intracell cholesterol increases LDL receptor synthesis
- stimulates ACAT to make cholesterol esters for storage
- low intracell cholesterol signals continued cholesterol synthesis
82
effects of absence of LDL receptors
- prevents uptake of LDL cholesterol
| - stimulates continued cholesterol synthesis
83
Tangier disease
rare metabolic disorder w/ defective ABCA1
| - extremely low levels of HDL -> cholesteorl accumulates in macrophages
84
ABCA1
ABC-binding cassette family of transporters - transports cholesterol out of macrophages into HDL
85
why is Tangier disease significant even though it is so rare?
revealed the role of ABC transporters in HDL metabolism
86
liver x receptor regulation
liver x receptor (LXR) and retinal x receptor (RXR) form a heterodimer transcriptional activator complex upon binding oxysterols (ex: 25-hydroxycholesterol)
87
when is expression of CETP and ABCA1 activated?
when cholesterol levels are high (and therefore oxysterols are high)
88
what besides LXR also forms heterodimers with RXR?
PPARa - regulates FA metabolism on binding specific lipids
89
diet therapy for high LDL
- reduced cholesterol, red meat
| - increased fruit, veggies, fish, whole grains
90
about how much can you reduce LDL levels by diet alone?
about 10%, but up to 25% w/ Mediterranean diet
91
statin therapy for high LDL
HMG-coA reductase inhibitors
- inhibit cholesterol biosynthesis
- lower intracell cholesterol -> stimulates synthesis of LDL receptors -> pulling more cholesterol from circulation
- lower total and LDL cholesterol
92
about how much do statins reduce CV death for patients w/ CHD?
30%
93
what are some statins?
- lovostatin
- pravastatin
- simvastatin
- fluvastatin
- atorvastatin
94
bile acid excretion therapy for high LDL
- cholestyramine
| - eztimibe/zetia
95
cholestyramine action
binds negatively charged bile acids in small intestine - increases bile excretion -> liver must convert more cholesterol to bile acids, increasing LDL uptake by liver -> lowers total and LDL cholesterol
96
eztimibe/zetia action
blocks bile acid absorption
97
general: potential therapies for high LDL
- diet therapy
- statins
- increase bile acid secretion (cholestyramine/eztimibe)
- fibrates
- nicotinic acid (B3)?
98
fibrates
agonists of PPARa - nuclear transcription factor
- activates transcription of many proteins in lipid metabolism
- increases proteins, leads to enhanced utilization of fat and reduction in lipoprotein particles
- lower TGs, total and LDL cholesterol
- may increase HDL cholesterol
99
examples of fibrates
- fenofibrate
| - gemfibrazil
100
how are fibrates typically used?
with statins
101
nicotinic acid therapy for high LDL
new study suggests no value - but, water soluble B vitamin that inhibits hormone sensitive lipase in adipose tissue, reducing plasma TGs -> reducing VLDL synthesis by liver
- increases HDL levels
- side effect: facial flushing
