Lecture 23: Cholesterol Synthesis & Lipid Transport Flashcards
1
Q
How many Cs in cholesterol? Where do they all come from?
A
27
All from acetate in acetyl CoA
2
Q
What are the 5 substrates in the cholesterol synthesis pathway?
A
2 Acetyl-coA => Acetoacetyl-coA => Mevalonate => Isoprene => Cholesterol
3
Q
What are the 3 uses for cholesterol once synthesized?
A
- Steroid hormones + vitamin D
- Cholesterol esters for storage/transport
- Bile acids
4
Q
What are the 2 ways of excreting cholesterol? Which is the main way? % contribution of each way?
A
- Bile acids (main way: 90%)
2. Steroid hormones (10%)
5
Q
Draw cholesterol.
A
INSERT PIC HERE
6
Q
Is cholesterol hydrophobic or hydrophilic?
A
VERY hydrophobic
7
Q
Describe the steps of cholesterol synthesis. 10 steps
A
- Thiolase: Acetyl CoA + Acetyl CoA = Acetoacetyl CoA + CoA-SH
- HMG-CoA synthase: Acetoacetyl CoA + Acetyl-CoA = HMG-CoA + CoA-SH
- HMG-CoA reductase: HMG-CoA + 2 NADPH = Mevalonate + 2 NADP+ + CoA-SH
- Mevalonate double phosphorylation on C5 from ATP = activated isoprene
- Phosphate added on C3 = immediate decarboxylation due to destabilization by the Pi
- Removal of C3 phosphate
- 2 isoprenes = geranyl pyrophosphate + isoprene pyrophphate = farnesyl pyrophosphate + farnesyl pyrophosphate + NADPH = squalene + NADP+ + 2 PPi
- Squalene monooxygenase: squalene + NADPH + O2 => squalene 2,3-epoxide + NADP+ + H2O
- Cyclase: squalene conversion to lanosterol
- Lanosterol conversion to cholesterol
8
Q
How many Cs in HMG-CoA?
A
6
9
Q
What is the main regulatory step of cholesterol synthesis?
A
Reduction of HMG-CoA by HMG-CoA reductase
10
Q
What do statin drugs inhibit? How do they work? How do different kinds differ?
A
They competitively inhibit HMG-CoA reductase as they have a similar structure to mevalonate
They have different R1 and R2 groups
11
Q
How many Cs in activated isoprenes?
A
5
12
Q
What is the full name of HMG-CoA?
A
β-hydroxy-β-methylglutaryl-CoA
13
Q
Other than for cholesterol synthesis, what can activated isoprenes be used to make?
A
- Lipid-soluble vitamins: A, E, K
- Carotenoids
- Rubber (in plants)
- Quinone electrons carriers
- Dolichols
- Phytol chain of chlorophyll
- Plant hormones: abscisic acid and gibberellic acid
14
Q
How many Cs in geranyl pyrophosphate?
A
10
15
Q
How many Cs in farnesyl pyrophosphate?
A
15
16
Q
How many Cs in squalene?
A
30
17
Q
What are stigmasterol and ergosterol?
A
Lipids similar in structure to cholesterol and synthesized through same pathway in plants (stigmasterol) and fungi (ergosterol) respectively
18
Q
In what form is cholesterol carried in HDLs in the blood? How is it formed?
A
Cholesterol ester formed by the addition of an FA from the 2’ of lecithin (=phosphatidylcholine) to the 3’ OH of cholesterol by the enzyme lecithin-cholesterol acyl transferase (LCAT) forming lysolecithin
19
Q
What are the 2 types of cholesterol carrier proteins?
A
- HDL
2. LDL
20
Q
In what form is cholesterol stored within cells? How is it formed?
A
Cholesterol ester formed by the addition of a free FA-CoA to the 3’ OH by the enzyme acyl-coA-cholesterol acyl transferase (ACAT) leaving CoA-Sh behind
21
Q
Where do we get most of our cholesterol?
A
We synthesize it!
22
Q
How much cholesterol is synthesized each day?
A
1 g
23
Q
How much cholesterol do we ingest each day?
A
0.3 g
24
Q
What are normal cholesterol blood levels?
A
150-200 mg/dL
25
Can you make all of the cholesterol you need via de novo synthesis?
YUP
26
Why is it really hard for us to control cholesterol levels?
Because if you stop eating cholesterol, you
| can still make it
27
What are the 4 ways of regulating cholesterol levels?
1. HMG-CoA reductase regulation
2. ACAT regulation
3. LDL/HDL ratios
4. Excretion as bile acids
28
What is the effect of high cholesterol levels on cholesterol synthesis? Is this called feedback inhibition?
Stimulation of proteolysis of HMG-CoA reductase: long-term feedback until new enzyme produced
NOT feedback inhibition because the enzyme is destroyed, not inhibited
29
What stimulates HMG-CoA reductase? How? Why?
Insulin (dephosphorylation) to stimulate fat storage when acetyl-CoA levels are high
30
What inhibits HMG-CoA reductase? How?
Glucagon: phosphorylation
31
How are LDL/HDL ratios regulated?
High cholesterol prevents the cells from taking up cholesterol by downregulating the LDL receptor and retaining it inside the cell to be degraded = it increases the LDL/HDL ratio
32
How is ACAT regulated?
High cholesterol will activate it so that free cholesterol is converted into cholesterol ester for storage
33
What is the precursor to vitamin D?
7-dehydrocholesterol
34
What mutation in Northern Europeans (Scandinavians) gives them an advantage or a disadvantage? What is this called?
Heterozygotes with a mutation in 7-DHC reductase allowing them to synthesize vitamin D without sunlight
Homozygotes cannot synthesize vitamin D at all so have deformities due to developmental defects: lack of meiosis activating C4-methylsterols (infertility) and 24,24-epoxycholesterol for midbrain development, but can still produce cholesterol through a different pathway
Smith-Lemli-Opitz syndrome
35
What are chylomycrons? What 5 types of molecules in them? Which one responsible for triggering TAG/cholesterol uptake?
Giant oil droplets containing :
1. TAGs
2. Cholesterol (free and esters)
3. Phospholipids
4. Apolipoproteins (triggers)
5. Lipid soluble vitamins ADEK + beta-carotene
36
What happens to the chylomicrons once they deliver TAGs to target cells? 3 steps
1. Liver collects them and repackages FAs into TAGs + cholesterol into VLDLs (very low density lipoproteins)
2. TAGs in VLDLs are broken down by lipoprotein lipases to be taken up by tissues => half of VLDLs remnants are taken up by tissues and half are sent to liver to be converted to LDLs (with more cholesterol than FAs)
3. Extrahepatic tissues send cholesterol back to the liver via HDLs
3. Liver collects HDLs
37
Which are responsible for heart disease: VLDLs or LDLs?
LDLs
38
How are fats (triacylglycerides) transported from the small intestine to target cells? 6 steps
1. Bile salts emulsify FAs so that they can access the more aqueous environment
2. Pancreas secretes lipases to degrade TAGs into FAs and glycerol
3. Mucosa takes up FAs + glycerol, re-esterifies them into TAGs, and packages them into chylomicrons
4. Chylomicrons travel through blood and lymph and bind to target tissues
5. Lipoprotein lipase activated by apoC-II to hydrolyze TAGs into FAs and glycerol IN SMALL CAPILLARIES AND ARTERIOLES for receptor-mediated absorption
6. TAGs are reformed
39
What is the main form of circulating cholesterol targeted for extrahepatic tissues?
LDL
40
Why is HDL is considered good cholesterol in comparison to LDL?
Because HDL means there is more cholesterol transported back to the liver rather than to the periphery: you are getting rid of the cholesterol within your cells (presupposing you had too much in them though)
41
Which is more dense: fat or proteins?
Proteins
42
Which is more dense: chylomicrons or VLDLs?
Same or chylomicrons a little less dense
43
List the lipoproteins in order of increasing DENSITY.
Chylomicrons => VLDLs => LDLs => HDLs
44
Which lipoprotein has the most TAGs?
Chylomicrons
45
Which lipoprotein has the most cholesterol?
LDLs
46
Which lipoprotein has the least TAGs?
HDLs
47
How are LDLs recognized for cholesterol uptake by cells? Describe the uptake.
ApoB-100 in LDLs is recognized and the LDL is taken up by receptor-mediated endocytosis forming an endosome which fuses with a lysosome and broken down into cholesterol, FAs, AAs, and then the receptor is recycled back to the surface
48
Are lipoprotein complexes simply a difference in the ratio of fatty acids and proteins?
No, because apolipoproteins are also involved and have different functions
49
For what purpose do cells take up lipoproteins?
1. AA synthesis
2. FA synthesis
3. Cholesteryl synthesis
4. Synthesis of compounds with cholesterol as their precursor
50
Where are bile acids synthesized?
Liver
51
Where are bile acids secreted? For what purpose?
In the intestine lumen to aid in fat absorption and to get rid of excess cholesterol
52
What are the 2 primary bile acids synthesized by the liver?
1. Chenodeoxycholic acid
| 2. Cholic acid
53
Where are bile acids stored?
Gallbladder
54
What are the 2 TYPES of bile acids? %?
1. Conjugated via amide bond to taurine or glycine: 98% = glycocholic acid and taurocholic acid
2. Unconjugated: 2%
55
When are conjugated bile acids converted to their free form?
In the intestine
56
How do bacteria in the intestine react with primary bile acids?
They convert them to secondary bile acids: 7-deoxycholic acid and lithocholate
57
Do both primary and secondary bile acids emulsify fats?
YUP
58
What % of bile salts are reabsorbed?
95%
59
What is the purpose of conjugating bile salts?
Because they are toxic to the liver/gallbladder so this neutralizes them
60
Describe the bile acid synthesis pathway. 2 steps
1. 7α-hydroxylase: cholesterol + NADPH + O2 => 7-hydroxycholesterol + NADP
2. 7-hydroxycholesterol + NADPH + O2 + 2 CoA-SH => cholyl-CoA OR chenodeoxycholyl-CoA + propionyl-CoA
61
What is the main control step of bile acid synthesis?
7α-hydroxylase
62
How can I recognize a bile acid?
Hydroxyl group on C7
63
How is 7α-hydroxylase regulated? What is the main controlling point?
1. CHOLESTEROL:
- High cholesterol = LXR α activation (nuclear hormone receptor) = 7α-hydroxylase activation
- Low cholesterol = 7α-hydroxylase inhibited through second messenger cascade (membrane receptors) and nuclear receptor activation
2. BILE ACIDS: primary and secondary
- Primary: second messenger cascade using JNK to interact with nuclear receptors: SHP, FXR, LXR to inhibit 7α-hydroxylase
- Secondary: bind PXR receptors to inhibit 7α-hydroxylase
Main controlling point: LXR
64
What can increase bile acid excretion? Why?
A meal rich in soluble fibers and ion-exchange resins like cholestyramine because they bind to bile acids
65
What does the liver do when it receives FFAs? 2 options
1. Collects them and repackages FAs into TAGs + cholesterol into VLDLs
2. FA beta oxidation to make acetyl-CoA for ketogenesis
66
Where does FA synthesis take place?
SER
67
How many rings in cholesterol?
4
68
How are double bonds named?
Delta-# of preceding C
69
What is ideal about how statins work?
They block synthesis around the start of the cholesterol biosynthesis or else there would be a lot of building of hydrophobic products => the precursors that do build up are water soluble and can be excreted easily
70
What are names of 2 activated isoprenes?
1. Δ3-isopentenyl pyrophosphate
| 2. Demethylallyl pyrophosphate
71
Is squalene linear or cyclic?
Linear
72
How is HMG-CoA reductase regulated?
1. Phosphorylation: decreases activity
| 2. Level of enzyme present
73
What's more efficient: eating less cholesterol or eating less?
Eating less because less insulin will be secreted, less cholesterol synthesis
74
Why would we want to inhibit cholesterol uptake by cells when there is too much?
Because cholesterol is toxic for cells
75
What is the last common substrate on the cholesterol synthesis between cholesterol and vitamin D?
7-dehydrocholesterol
76
What does it mean for a lipoprotein to have lower density?
More fats!
77
What apolipoprotein is responsible for triggering the activation of LCAT?
ApoA-I
78
What needs to happen to bile acids before they get conjugated?
Addition of CoA through the cholesterol synthesis pathway
79
How would a disease causing misabsorption of fats affect cholesterol in the body?
Excreting MORE cholesterol through bile acids, so you would have LESS cholesterol
80
At which C are glycine and taurine attached to conjugated bile acids?
C24
81
What does the prefix oxo- mean?
Ketone
82
What does it mean for steroids to be synthesized in situ?
They synthesize their own cholesterol to synthesize the steroids
83
What 3 hormones stimulate esterase to liberate cholesterol from the lipid droplets in the cell?
1. ACTH
2. LH
3. Angiotensin II
84
What is congenital lipoid adrenal hyperplasia due to? 5 Symptoms?
Mutations in StAR cause decreased steroidogenesis and excess cholesterol in adrenal cortex causes cellular damage
1. Salt wasting
2. Hyperkalemia
3. Hypovolemia
4. Acidosis
5. Death in infancy if not treated
85
What is hyponatremia?
Not enough sodium in blood
86
Why are alcoholics more prone to candida yeast infections?
Candida can use alcohol as energy by making it into acetaldehyde and then acetaldehyde dehydrogenase reduces it further into acetic acid, which can be made into acetyl-CoA
87
How does fluconazole work to treat yeast infections?
It's a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14- α-demethylase which functions to convert lanosterol to ergosterol, a fungi lipid
88
What can low cholesterol levels indicate?
Vitamin D deficiency
89
Describe the release of bile acids in the intestine.
Pulsatile release.
90
What are 2 foods rich in soluble fibers which can reduce cholesterol levels?
1. Oats
| 2. Chia seeds
