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Biochemistry II > Cholesterol, bile > Flashcards

Cholesterol, bile Flashcards

1
Q

What are the functions of cholesterol?

How is it stored in the body?

A

stored as cholesterolester

functions:

  • important part of cellular membranes
  • precursor of steroid hormones
  • precursor of bile acids
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2
Q

How much cholesterol can be found in the body?

Where?

A

in total 140g (70kg human)

  • 120g in membranes
  • 10g in blood plasma

rest… ?

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3
Q

How much cholesterol is supplied and lost daily?

A

supply:

  • 0.5g synthesized in liver
  • 0.5g synthesized in extrahepatic tissue
  • 0.5g dietary intake

loss:

  • 0.5g synthesized to bile salts
  • 0.5g free cholesterol in bile
  • 0.5g desquamation of epithelium
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4
Q

Where can cholesterol be found in the membrane?

A

hydrophilic OH- group at aqueous interface,
remainder within lipid bilayer leaflet

  • btw phospholipids
  • esp. abundant in lipid-rafts and caveolae
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5
Q

What are the 5 steps of cholesterol synthesis?

A
  1. mevalonate formed from acetyl-CoA
  2. active isoprene, isopentenyl PP formed by loss of CO2
  3. condensates to squalene
  4. cyclizes to parent steroid lanosterol
  5. formation of cholesterol
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6
Q

How much energy and acetyl-CoA is needed to produce 1 molecule of cholesterole?

How many enzymes are involved?

A
  • 18 acetyl-CoA
  • 36 ATP
  • 20 NADPH/H+
  • 21 enzymes
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7
Q

Describe the stepwise production of mevalonate.

Where does it happen?

Enzymes + reactions.

A

first 2 steps of ketogenesis, BUT: in cytosol

  1. thiolase
    2acetyl-CoA → acetoacetyl-CoA + CoA-SH
  2. HMG-CoA synthase
    … + acetyl-CoA → HMG-CoA + CoA-SH
  3. HMG-CoA reductase
    … + 2NADPH/H+ → CoA-SH + 2NADP+ + mevalonate
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8
Q

What is special about HMG-CoA reductase?

Where can it be found?

A

catalyzes rate-limiting step of cholesterol synthesis

→ anchored to membrane of ER
(considered as enzyme of ER)

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9
Q

How is isopentenyl PP formed?

Anything important?

Structure.

A

mevalonate phosphorylated sequentially, after decarboxylation → isopentenyl PP

3 ATP used, 1 CO2 formed

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10
Q

How is squalene formed?

Structure.

A

formed from 6 isopentenyl PP

  1. isopentenyl PP isomerizes
  2. condensates w/ another isopentenyl PP → geranyl PP (10C)
  3. condensates w/ another isopentenyl PP → farnesyl PP (15C)
  4. 2 farnesyl PP → squalene (30C), 1NADPH/H+ used

Farnesyl (<u><strong>F</strong></u>ifteen)

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11
Q

How is lanosterol formed?

Where does it happen?

Structure.

A
  1. squalene converted to squalene 2,3-epoxide in the ER
  2. ring closure to form steroid nucleus, lanosterol
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12
Q

How is cholesterol formed?

Where does it happen?

Structure.

A

lanosterol undergoes changes in steroid nucleus + side chain → cholesterol

happens on ER membrane

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13
Q

Explain the general mechanism of cholesterol homeostasis.

A

cholesterol concentration more or less constant bc regulated via synthesis/excretion

  • ↑ cholesterol → ↓ transcription of
    • HMG-CoA synthase
    • HMG-CoA reductase
    • prenyltransferase
    • genes coding LDL receptor
  • ↓ cholesterol → ↑ transcription
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14
Q

What is the function of SRBEP?

Describe its structure.

A

3 isoenzymes: SREBP-1a, -1c, 2
→ SREBP-2 causes transcription of enzymes involved in cholesterol synthesis

3 domains:

  • N-terminal: transcription factor, helix-loop-helix (HLH)
  • C terminal: regulatory function, binding to SCAP
  • luminal domain: incorporated in ER membrane
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15
Q

Which 2 enzymes show cholesterol sensor domains?

A
  • HMG-CoA reductase: produces mevalonate, catalyzes committed step of chol. synthesis
  • SCAP: SREBP cleavage-activating protein, bound to ER membrane, interacts w/ C-terminal of SRBEP-2
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16
Q

How is the activity of HMG-CoA reductase regulated?

Why is it so important?

A

catalyzes committed step of cholesterol synthesis, regulated by

  • [cholesterol]
  • oxysterol binding
  • reversible phosphorylation
  • competitive inhibition
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17
Q

Explain how HMG-CoA reductase is regulated by the cholesterol concentration.

A
  • ↑ [cholesterol]: binding to SCAP → SRBEP-2/SCAP complex binds to insig → complex remains attached to ER membrane
  • ↓ [cholesterol]: SRBEP-2/SCAP complex able to translocate to Golgi → interaction w/ proteases S1P, S2P
18
Q

Explain the function of S1P and S2P.

A

↓ [cholesterol] → SREBP-2/SCAP complex translocated to Golgi membrane

  1. S1P: cleaves luminal domain of SRBEP-2, but still bound in Golgi membrane
  2. S2P: releases HLH domain (N-terminal of SREBP-2), translocates into nucleus → transcription of coded genes

⇒ ↓ [cholesterol] → ↑ HMG-CoA reductase expression
⇒ ↑ cholesterol synthesis

19
Q

Explain how HMG-CoA reductase is regulated by oxysterols.

A

able to bind to HMG-CoA reductase
→ target for ubiquitination ​→ ↓ [HMG-CoA reductase]

⇒ ↓ cholesterol synthesis

20
Q

Explain how HMG-CoA reductase is regulated by reversible phosphorylation.

A

phosphorylated (= inactivated) by AMPK in response to

  • glucagon, glucocorticoids via direct phosphorylation, and phosphorylation of AMPKK
  • AMP binding to AMPK

dephosphorylated (= activated) by phosphatase in response to

  • insulin
  • thyroid hormones

→ inactivated when E deficit in cell
⇒ ↓ cholesterol synthesis

​

21
Q

Explain how HMG-CoA reductase is regulated by competitive inhibition.

Clinical importance?

A

mevalonate = competitive inhibitor (product inhibition)

→ statins structurally similar to mevalonate, very high affinity

⇒ completely stop cholesterol synthesis

22
Q

How are cholesterol, resp. cholesterolesters taken up from the intestinal lumen into the body?

A
  1. hydrolysis of CE to cholesterol in lumen
  2. uptake of free cholesterol through Niemann-Pick C1-like protein 1 (NPC1L1)
  3. resynthesis to CEs by ACAT 2

→ CE packed into chylomicrons

23
Q

What happens w/ sterols taken up via NPC1L1?

A

sorted in endosome, then excreted again via ABCG5 and 8

24
Q

What is the function of ACAT?

Reaction.

Distinguish btw ACAT 1 and ACAT 2.

A

acyl-CoA:cholesterol acyltransferase
produces cholesterol esters for intracellular storage of cholesterol

acyl-CoA + cholesterol ⇔ CoA-SH + cholesterol ester

  • ACAT 1: in macrophages
  • ACAT 2: in intestine, liver
25
Which 2 mechanisms are intracellulary activated by cholesterol?
* **decr. cholesterol synthesis** via SREBP-2 pathway * **activates ACAT** **allosterically** → stored as cholesterolester
26
What is the function of the LDL receptor? Which group of drugs regulate its expression?
_determines LDL level in blood_ ↑ [LDL receptor] → ↓ blood cholesterol level induced by **statins** _NOTE:_ statins also inhibit HMG-CoA reductase comp.
27
What is the function of PCSK9?
**_proprotein convertase subtilisin/kexin type 9_** regulates LDL receptor recycling by **targeting it for degradation** ⇒ ↓ LDL uptake → ↑ blood cholesterol level
28
What does IDOL do?
**_inducible degrader_** _of the_ **_LDL receptor_** ubiquitin ligase that is induced by intracellular cholesterol ⇒ **degradation of LDL receptor →** ↑ blood cholesterol level
29
How is cholesterol excreted?
converted to _bile acids_ in liver (b/c otherwise cholesterol would be non-water soluble), then secreted into duodenum, eventually parts of it excreted in feces _NOTE:_ majority is reabsorbed in ileum = **enterohepatic circulation**
30
Distinguish btw primary and secondary bile acids.
_primary bile acids_ are synthesized from cholesterol in the liver, then _conjugated_, secreted into duodenum and metabolized to _secondary bile acids_ by intestinal bacteria * **cholic acid** → **deoxycholic acid** * **chenodeoxycholic acid** → **lithocholic acid**
31
What are bile salts?
since bile is usually **slightly alkaline** (pH 7.6 - 8.4), _bile acid and their conjugates_ are assumed to be in **salt form**
32
As an overview.. Which coenzymes and type of enzymes are required for bile acid synthesis?
* coenzymes: **NADPH, NADH, CoA** * enzymes: **hydroxylases** (CYP 450 dependent), **dehydrogenases**, **isomerases**
33
Which enzyme catalyzes the first step of bile synthesis? Reaction + cofactor. Why is it especially important?
common step of both primary bile acids **_7α-hydroxylase (CYP7A1)_** **cholesterol + NADPH + O2 → NADP+ + 7α-dehydroxycholesterol** _NOTE:_ requires vit C as cofactor important b/c **principal regulatory step**
34
List the remaining steps of bile acid synthesis, once 7α-hydroxycholesterol is formed.
1. sevel steps to produce primary bile acids: * **cholic acid** * **chenodeoxycholic acid** 2. are _conjugated_ w/ **taurine or glycine** to form * tauro-/glycocholic acid * tauro-/glycochenodeoxycholic acid 3. are _deconjugated_ and _7α-dehydroxylated_ to form secondary bile acids: * **deoxycholic acid** * **lithocholic acid**
35
List the hydroxylation sites of both primary and secondary bile acids
* **cholic acid**: 3α, 7α, 12α → **deoxycholic acid**: 3α, 12α * **chenodeoxycholic acid:** 3α, 7α **→ lithocholic acid**: 3α
36
What are the 2 functions of bile acids?
* _incr. the activity_ of **pancreatic lipase** * _incr. the surface are__a_ of emulsified lipid droplets by forming **mixed bile acid-phospholipid micelles**
37
Which phospholipid is especially abundant in mixed micelles?
**phosphatidylcholine** (= lecithin)
38
How is 7α dehydroxylase regulated?
* _inhibited_ by **bile acids** * _transcription downregulated_ by **SHP** * _transcription upregulated_ by **LXR**
39
Which 2 nuclear receptors play a role in the regulation of bile acid (ergo cholesterol) levels?
* **LXR** = liver X receptor * **FXR** = farnesoid X receptor **​**= metabolite receptors
40
Explain the function of LXR. Overall effect.
_liver X receptor_ 1. when **oxysterols** (formed when _high levels of cholesterol_ present) bind to LXR 2. LXR forms **heterodimer w/ RXR** 3. _incr. transcription_ of: * **CYP7A1** * **ABCA1** * **IDOL** ⇒ incr. bile acid synthesis, cholesterol efflux and decr. the expression of LDL-Rs to prevent cholesterol overload of cells
41
Explain the function of the FXR. Overall effect?
_farnesoid X receptor_ when **bile acids** accumulate (i.e. due to cholestasis), incr. transcription of * **PCSK9** * **SHP** * **BSEP, MRP2:** canalicular transporters **​**⇒ incr. bile excretion and degradation of LDL-R (+ SHP effects)
42
What is the function of SHP?
_small heterodimer protein_ 1. enhanced transcription of SHP **if FXR is active** in response to binding of bile acids 2. binds to transcription factors, forming a **heterodimer + blocking their acivity** 3. causes _decr. expression of__​​_ **CYP7A1** ​→ decr. bile acid synthesis

Biochemistry II (16 decks)

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