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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
Q

Which 2 mechanisms are intracellulary activated by cholesterol?

A
  • decr. cholesterol synthesis via SREBP-2 pathway
  • activates ACAT allosterically → stored as cholesterolester
26
Q

What is the function of the LDL receptor?

Which group of drugs regulate its expression?

A

determines LDL level in blood
↑ [LDL receptor] → ↓ blood cholesterol level

induced by statins

NOTE: statins also inhibit HMG-CoA reductase comp.

27
Q

What is the function of PCSK9?

A

proprotein convertase subtilisin/kexin type 9

regulates LDL receptor recycling by targeting it for degradation

⇒ ↓ LDL uptake → ↑ blood cholesterol level

28
Q

What does IDOL do?

A

inducible degrader of the LDL receptor

ubiquitin ligase that is induced by intracellular cholesterol

⇒ degradation of LDL receptor → ↑ blood cholesterol level

29
Q

How is cholesterol excreted?

A

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
Q

Distinguish btw primary and secondary bile acids.

A

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
Q

What are bile salts?

A

since bile is usually slightly alkaline (pH 7.6 - 8.4), bile acid and their conjugates are assumed to be in salt form

32
Q

As an overview..

Which coenzymes and type of enzymes are required for bile acid synthesis?

A
  • coenzymes: NADPH, NADH, CoA
  • enzymes: hydroxylases (CYP 450 dependent), dehydrogenases, isomerases
33
Q

Which enzyme catalyzes the first step of bile synthesis?

Reaction + cofactor.

Why is it especially important?

A

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
Q

List the remaining steps of bile acid synthesis, once 7α-hydroxycholesterol is formed.

A
  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
Q

List the hydroxylation sites of both primary and secondary bile acids

A
  • cholic acid: 3α, 7α, 12α
    → deoxycholic acid: 3α, 12α
  • chenodeoxycholic acid: 3α, 7α
    → lithocholic acid: 3α
36
Q

What are the 2 functions of bile acids?

A
  • incr. the activity of pancreatic lipase
  • incr. the surface are__a of emulsified lipid droplets by forming mixed bile acid-phospholipid micelles
37
Q

Which phospholipid is especially abundant in mixed micelles?

A

phosphatidylcholine (= lecithin)

38
Q

How is 7α dehydroxylase regulated?

A
  • inhibited by bile acids
  • transcription downregulated by SHP
  • transcription upregulated by LXR
39
Q

Which 2 nuclear receptors play a role in the regulation of bile acid (ergo cholesterol) levels?

A
  • LXR = liver X receptor
  • FXR = farnesoid X receptor

​= metabolite receptors

40
Q

Explain the function of LXR.

Overall effect.

A

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
Q

Explain the function of the FXR.

Overall effect?

A

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
Q

What is the function of SHP?

A

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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