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Biochem - Exam 2 > Cholesterol Metabolism > Flashcards

Cholesterol Metabolism Flashcards

1
Q

cholesterol synthesis pathway

A

acetyl coA -> mevalonate -> 3-isopentyl pyrophosphate -> cholesterol

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2
Q

how is cholesterol transported?

A

by VLDL, LDL, HDL

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3
Q

what is associated with reduced adverse CV events in middle age people?

A

reduced LDL and elevated HDL

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4
Q

what inhibits cholesterol synthesis?

A

cholesterol - feedback inhibition

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5
Q

what is cholesterol used to make?

A

vitamin D, bile salts, steroid hormones

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6
Q

what enzyme turns acetyl coA into mevalonate?

A

HMG-coA reductase

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7
Q

what happens to cholesterol levels as you age?

A

tend to increase w/ age, then stabilize around 60

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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
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9
Q

cholesterol synthesis requires large amounts of what reducing equivalents?

A

NADPH

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10
Q

what are the two types of HMG-coA synthase?

A

mitochondrial (ketone bodies) and cytoplasmic (cholesterol)

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11
Q

HMG coA synthesis

A

acetyl coA -> acetoacetyl coA -> HMG-coA

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12
Q

rate limiting step in cholesterol synthesis

A

3-hydroxy-3-methylglutaryl-coA -> mevalonate

-done by HMG-coA reductase, uses 2 NADPH

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13
Q

statins

A

competitive inhibitors of HMG-coA reductase - lower plasma cholesterol levels

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14
Q

what are potential side effects of statins?

A

myopathy and rhabdomyolysis

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15
Q

what are the enzymes for the three reactions converting mevalonate into isopentenyl pyrophosphate?

A
  1. mevalonate 5’ phosphokinase
  2. phosphomevalonate kinase
  3. pyrophosphomevalonate decarboxylase
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16
Q

what two substances is isopentenyl pyropyrophosphate used to make?

A

cholesterol and ubiquinone (coQ)

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17
Q

polymerization of isopentenyl-PP

A

isopentenyl-PP + dimethylallyl-PP (C5 isoprenes) -> geranyl-PP (C10 polyisoprene) -> farnesyl-PP (C15 polyisoprene) -> squalene (C30 polyisoprene)

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18
Q

where might you find geranyl-PP and farnesyl-PP?

A

may see as oncogenes attached to membranes

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19
Q

cyclization and isomerization

A

squalene -> squalene epoxide -> lanosterol -> (19 steps) -> cholesterol

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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)
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21
Q

what are the major sites for cholesterol synthesis?

A

liver and intestine

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22
Q

SCAP

A

SREBP cleavage-activating protein

  • binds cholesterol and other sterols
  • moves to golgi in absence of cholesterol binding
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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
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24
Q

where are bile acids synthesized?

A

liver

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25
Q

rate-limiting step of bile synthesis

A

CYP7A1 places OH on C7 (O2 and NADPH)

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26
Q

what makes bile acid amphipathic?

A

carboxyl group on side chain of steroid ring

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27
Q

how are bile acids converted to salts?

A

Add Gly or taurine (amide bond)

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28
Q

how much bile does a typical adult liver produce daily?

A

0.5 - 1 L

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29
Q

what is CYP7A1 inhibited by?

A

bile salts

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30
Q

what do bacteria do to bile salts?

A

deconjugate them, remove 7-OH to produce secondary bile salts

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31
Q

bile composition

A
  • water
  • cholesterol
  • bile salts
  • bilirubin
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32
Q

what is cholesterol solubilized by?

A

phospholipids, bile salts

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33
Q

what is the composition of 80% of US gallstones?

A

cholesterol stones

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34
Q

factors for cholesterol gallstones

A
  1. bile acid levels
  2. biliary cholesterol secretion
  3. gallbladder hypomotility
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35
Q

how are cholesterol esters transported in blood?

A

as FA esters

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36
Q

LCAT

A

lecithin: cholesterol acyltransferase
- in blood
- esterifies HDL cholesterol, so it is retained in particles

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37
Q

what is lecithin?

A

a phosphatidylcholine

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38
Q

ACAT

A

acyl: cholesterol acyltransferase
- intracellular
- packages cholesterol for VLDL and storage in liver for bild production

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39
Q

CETP

A

cholesterol ester transfer protein

-HDL to VLDL transfer of cholesterol

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40
Q

what do chylomicrons transport?

A

dietary TGs

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41
Q

where are chylomicrons synthesized?

A

epithelial cells of intestine

42
Q

chylomicrons compared to other plasma lipoprotein particles

A
  • least dense

- highest TGs

43
Q

what two apolipoproteins are associated with chylomicrons?

A

ApoB-48 and ApoC-II and ApoE

44
Q

what happens when chylomicrons are depleted of TGs?

A

ApoE is exposed and binds to receptors on liver - cholesterol is released

45
Q

what do VLDLs transport?

A

endogenous TGs

46
Q

VLDL production

A

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
Q

is there any cholesterol in VLDLs?

A

yes - some cholesterol and cholesterol esters

48
Q

apolipoproteins associated w/ VLDLs?

A

ApoB-100, ApoC-II, ApoE

49
Q

fate of VLDLs

A

50%: remnants removed via ApoE receptor mediated endocytosis in liver
50%: VLDL -> IDL -> LDL

50
Q

what does LDL transport?

A

cholesterol transport to extrahepatic tissues

51
Q

is there any cholesterol in LDLs?

A

yes - rich in cholesterol and cholesterol esters

52
Q

apolipoproteins associated w/ LDLs?

A

ApoB-100

53
Q

which is the bad cholesterol: HDLs or LDLs?

A

LDLs

54
Q

what do HDLs transport?

A

reverse cholesterol transport (tissues to liver)

55
Q

where are HDLs formed?

A

liver or small intestine

56
Q

is there any cholesterol in HDLs?

A

nascent has very little cholesterol

57
Q

apolipoproteins associated with HDLs?

A

ApoA-1, ApoC-II, ApoE

58
Q

what does ApoA-1 activate?

A

LCAT

59
Q

what does LCAT generate cholesterol esters from?

A

cholesterol and phosphatidylcholine

60
Q

what do HDL particles bind to unload cholesterol to liver (how are HDLs cleared)?

A

scavenger receptor-B1

61
Q

what does LDL receptor recognize?

A

apoE and apoB-100

62
Q

what does LDL receptor bind?

A

VLDL, LDL, IDL, chylomicron remnants

63
Q

what does LDL receptor deficiency cause?

A

high blood cholesterol

64
Q

LRP

A

LDL receptor related protein

65
Q

where is LRP found?

A

liver, brain, placenta

66
Q

what does LRP bind?

A

apoE - clears remnants?

67
Q

LRP expression regulation

A
  • independent of [cholesterol]

- increases in response to insulin

68
Q

what does SR-B1 bind?

A

HDL

69
Q

what does SR-A1 or SR-A2 bind?

A

oxidized LDL (superoxide)

70
Q

where are SR-A1 and -A2 found?

A

on macrophages

71
Q

scavenger receptor expression regulation

A

-independent of [cholesterol]

72
Q

foam cells

A

macrophage engorged with lipid

73
Q

how does HDL accept cholesterol from peripheral tissue?

A

via ABC A1

74
Q

how does HDL retain cholesterol?

A

esterification by LCAT

75
Q

what results from inhibiting CETP?

A

raises HDL

76
Q

familial hypercholesterolemia (FH) cause

A

defective LDL receptor:
heterozygotes - 200-400 mg/dL serum cholesterol
homozygotes - 500-800 mg/dL serum cholesterol

77
Q

xanthomas

A

deposition of cholesterol rich material on tendons

-in het adults and homo children

78
Q

corneal arcus

A

white line on edge of cornea - in homo children

79
Q

FH symptoms

A
  • high incidence of coronary artery disease
  • xanthomas
  • corneal arcus
80
Q

familial ligand defective apoB-100 (FLDB)

A
  • 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
Q

effect of cholesterol uptake on cholesterol regulation

A
  • 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
Q

effects of absence of LDL receptors

A
  • prevents uptake of LDL cholesterol

- stimulates continued cholesterol synthesis

83
Q

Tangier disease

A

rare metabolic disorder w/ defective ABCA1

- extremely low levels of HDL -> cholesteorl accumulates in macrophages

84
Q

ABCA1

A

ABC-binding cassette family of transporters - transports cholesterol out of macrophages into HDL

85
Q

why is Tangier disease significant even though it is so rare?

A

revealed the role of ABC transporters in HDL metabolism

86
Q

liver x receptor regulation

A

liver x receptor (LXR) and retinal x receptor (RXR) form a heterodimer transcriptional activator complex upon binding oxysterols (ex: 25-hydroxycholesterol)

87
Q

when is expression of CETP and ABCA1 activated?

A

when cholesterol levels are high (and therefore oxysterols are high)

88
Q

what besides LXR also forms heterodimers with RXR?

A

PPARa - regulates FA metabolism on binding specific lipids

89
Q

diet therapy for high LDL

A
  • reduced cholesterol, red meat

- increased fruit, veggies, fish, whole grains

90
Q

about how much can you reduce LDL levels by diet alone?

A

about 10%, but up to 25% w/ Mediterranean diet

91
Q

statin therapy for high LDL

A

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
Q

about how much do statins reduce CV death for patients w/ CHD?

A

30%

93
Q

what are some statins?

A
  • lovostatin
  • pravastatin
  • simvastatin
  • fluvastatin
  • atorvastatin
94
Q

bile acid excretion therapy for high LDL

A
  • cholestyramine

- eztimibe/zetia

95
Q

cholestyramine action

A

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
Q

eztimibe/zetia action

A

blocks bile acid absorption

97
Q

general: potential therapies for high LDL

A
  • diet therapy
  • statins
  • increase bile acid secretion (cholestyramine/eztimibe)
  • fibrates
  • nicotinic acid (B3)?
98
Q

fibrates

A

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
Q

examples of fibrates

A
  • fenofibrate

- gemfibrazil

100
Q

how are fibrates typically used?

A

with statins

101
Q

nicotinic acid therapy for high LDL

A

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

Biochem - Exam 2 (5 decks)

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