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Tissues > T09 - Cholesterol Biosynthesis > Flashcards

T09 - Cholesterol Biosynthesis Flashcards

1
Q

Which tissues of the body contains the most cholesterol, on an mg/g basis? List the top four.

A

brain > adrenal > lung > kidney

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2
Q

What are the three ways by which tissues obtain cholesterol?

A

de novo synthesis from acetate

uptake of cholesterol-rich lipoproteins

diet

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3
Q

How many carbons does cholesterol have?

A

27

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4
Q

How many steps does cholesterol synthesis take?

A

18

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5
Q

How does progressing along the cholesterol synthesis pathway affect solubility?

A

solubility in water of successive intermediates decreases as cholesterol is assembled

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6
Q

What is the rate-limiting enzyme in cholesterol synthesis?

A

HMG-CoA reductase

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7
Q

What regulates HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis?

A

SREBP family of proteins which are transcription factors

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8
Q

SLOS syndrome is caused by

A

a defect in Δ7-sterol reductase, the last enzyme in the cholesterol synthesis pathway

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9
Q

The brain, out of all other tissues, contains the most cholesterol in the body. What is this cholesterol used for?

A

cholesterol is located in myelin sheaths

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10
Q

How is the brain unique in its cholesterol utilization?

A

it can only synthesize cholesterol de novo because of the blood/brain barrier

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11
Q

How do cells choose between receptor-mediated endocytosis of cholesterol and de novo synthesis of cholesterol?

A

cells prefer LDLR over de novo synthesis (exception: muscle cells, which have low LDL receptors, tend to make their own cholesterol)

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12
Q

What are the two pathways by which cholesterol is metabolized in mammalian cells?

A

cholesterol → bile acids (95% of the time)

cholesterol → steroid hormones (5% of the time)

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13
Q

Describe the mammal’s preference for using acetate to produce fatty acids vs. to produce cholesterol.

A

10x more fatty acid synthesis than cholesterol synthesis

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14
Q

Where is HMG-CoA reductase located?

A

located in the membrane of ER

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15
Q

Write out the first six reactions of the cholesterol synthesis pathway. Identify where HMG-CoA reductase acts.

A

acetyl-CoA → acetoacetyl-CoA → HMG-CoA → [HMG-CoA reductase] → mevalonate →→→ farnesyl pyrophosphate → squalene →→→

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16
Q

Differentiate between the Bloch and Kandutsch-Russel pathways of cholesterol synthesis.

A

Bloch = liver = higher amounts of lanosterol 14-demethylase

Kandutsch-Russel = skin = higher amounts of Δ24-sterol, dictated by need to synthesize 7-dehydrocholesterol, a precursor of vitamin D3

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17
Q

(T/F) The steps of cholesterol synthesis differ based on tissue.

A

True

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18
Q

Describe the characteristics of the intermediates of cholesterol synthesis.

A

7 water soluble intermediates

4 isoprenoid intermediates

7 sterol intermediates

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19
Q

What is triparanol and how does it act?

A

drug that inhibits the 2nd last to step of cholesterol synthesis → accumulation of hydrophobic intermediates → toxic

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20
Q

Which is more harmful — mutations to enzymes earlier in the cholesterol synthesis pathway, or mutations to enzymes later in the pathway?

A

mutations to enzymes later in the pathway are more harmful

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21
Q

Where are enzymes associated with cholesterol synthesis located in the cell?

A

located in either cytosol or ER

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22
Q

What are the two major pathways of cholesterol synthesis?

A

Bloch pathway (liver)

Kandutsch-Russel pathway (skin)

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23
Q

What is an alternative fate of isopentenyl pyrophosphate, a cholesterol synthesis intermediate?

A

aromatic compound

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24
Q

What is an alternative fate of dolichols, a cholesterol synthesis intermediate?

A

protein glycosylation

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25
Q

What is an alternative fate of quinone, a cholesterol synthesis intermediate?

A

electron transfer

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26
Q

Isopentenyl pyrophosphate, a cholesterol synthesis intermediate, can be converted to which compounds/vitamins?

A

vitamins A/E/K

dolichols

quinones

27
Q

What is the precursor to vitamin D3?

A

7-dehydrocholesterol

28
Q

The conversion of 7-dehydrocholesterol to vitamin D3 is a multi-step process. Where does the first step take place?

A

skin

29
Q

Describe what happens in the first step of vitamin D3 formation.

A

non-enzymatic: exposure to UV light causes scission of B-ring of 7-dehydrocholesterol to form previtamin D → undergoes isomerization over 36 hours → produces vitamin D3

30
Q

Is vitamin D3 active after it is formed from 7-dehydrocholesterol?

A

No, it is inactive and has to be hydroxylated twice to become active

31
Q

Where does the first hydroxylation of inactive/unmodified vitamin D3 take place?

A

liver

32
Q

What enzymes mediate the first hydroxylation of inactive/unmodified vitamin D3?

A

CYP2R1 -or- CYP27A1

33
Q

Where does the second hydroxylation of inactive/unmodified vitamin D3 take place?

A

kidney

mono-hydroxylated vitamin D3 transported by vitamin D binding protein from liver → kidney

34
Q

What enzymes mediate the second hydroxylation of inactive/unmodified vitamin D3?

A

only CYP27B1

35
Q

What is the product of the second hydroxylation of inactive/unmodified vitamin D3? What does this compound do?

A

1α,25-dihydroxyvitamin D3

binds to activates vitamin D receptor, which regulates transcription of vitamin D3 target genes that control calcium metabolism

36
Q

Describe the half-life of 1α,25-dihydroxyvitamin D3.

A

1α,25-dihydroxyvitamin D3 is quickly inactivated by enzymes in vitamin D target tissues, so its blood levels are very low

37
Q

Which form of vitamin D3 is clinically measured?

A

25-hydroxyvitamin D3 (the immediate precursor to 1α,25-dihydroxyvitamin D3)

38
Q

What increases plasma levels of 25-hydroxyvitamin D3?

A

increased exposure to sunlight

increased dietary intake of vitamin D

39
Q

Write out the steps of the vitamin D3 synthesis pathway. (6)

A

7-dehydrocholesterol → [UV] → previtamin D → [36 hrs] → vitamin D3 → [CYP27A1/CYP2R1] → 25-hydroxyvitamin D3 → [CYP27B1] → 1α,25-dihydroxyvitamin D3

40
Q

Mutations in the genes that produce vitamin D3 cause what disease?

A

rickets

41
Q

When cells were sated for cholesterol, but were fed excess cholesterol, what were the three possible outcomes?

A

reduction in levels of HMG-CoA reductase

stimulated ACAT (cholsterol → cholesteryl esters)

reduced LDLRs

42
Q

What are the two forms of post-translational regulation of HMG-CoA reductase?

A

geranylgeranyl pyrophosphate

24,25-dihydrolanosterol

(both intermediates in the cholesterol synthesis pathway)

43
Q

What is the one form of transcriptional regulation of HMG CoA reductase?

A

cholesterol inhibits SREBPs, and SREBPs are needed to activate cholesterol synthesis

44
Q

Write out the pathway of events that occur when 24,25-dihydrolanosterol builds up. (6)

A

24,25-dihydrolanosterol builds up → activate Insig → binds to HMG-CoA reductase in ER membrane → HMG-CoA ubiquitinated → geranylgeranyl pyrophosphate extracts ubiquitinated HMG-CoA → ubiquitinated HMG-CoA degraded by proteasome

45
Q

Where are SREBPs made?

A

made as precursor proteins in ER

46
Q

Write out the pathway of events involving SCAP and SREBP that occur when a cell is starved for cholesterol. (5)

A

SCAP dissociates from Insig → SCAP escorts SREBP to Golgi → SREBP cut in half → amino-terminal half containing DNA-binding domain migrates to nucleus → activates enzymes for cholesterol synthesis

47
Q

Write out the pathway of events involving SCAP and SREBP that occur when a cell has excess cholesterol.

A

cholesterol binds to SCAP → SCAP binds to Insig → SCAP/SREBP complex can’t move to Golgi → SREBP can’t be activated

48
Q

Describe the half life of HMG CoA reductase.

A

short half-life

49
Q

Statins inhibit

A

HMG-CoA reductase

50
Q

Why are there so many different statins? (2)

A

(1) different statins have different potency in reducing levels of LDL-cholesterol
(2) different patients respond differently to different statins

51
Q

What are two conditions that lead to a Class I statin recommendation?

A

LDL-C > 190 mg/dL → start on high-intensity statin

or

DM + age 40-75 → start on moderate-intensity statin

52
Q

In ASCVD prevention and risk assessment, how do you treat patients age 0-19? (2)

A

counsel on lifestyle to prevent ASCVD

if diagnosed with familial hypercholesterolemia → start on statin

53
Q

In ASCVD prevention and risk assessment, how do you treat patients age 20-39?

A

counsel on lifestyle to prevent ASCVD

if family hx of premature ASCVD AND LDL-C > 160 mg/dL → start on statin

54
Q

In 40-75 year old patients who have LDL-C between 70 and 190 mg/dL, but no hx of DM, what are the possible statin treatment options?

A

low risk - discuss risks and counsel on lifestyle

borderline risk - discuss risks and consider starting moderate-intensity statin

intermediate risk - start moderate-intensity statin to reduce LDL-C by 30%

high risk - start statin to reduce LDL-C by 50%

55
Q

What is the clinical presentation of Smith-Lemli-Opitz Syndrome? (4)

A

feeding problems

mental retardation

microcephaly

polydactyly

56
Q

What is the inheritance pattern of Smith-Lemli-Opitz Syndrome?

A

autosomal recessive

57
Q

On a cellular level, why is Smith-Lemli-Opitz Syndrome harmful?

A

leads to accumulation of 7-dehydrocholesterol, which means not enough cholesterol is produced

58
Q

How is Smith-Lemli-Opitz Syndrome diagnosed? (2)

A

gene sequencing

measurement of 7-dehydrocholesterol in blood

59
Q

What is the treatment of Smith-Lemli-Opitz Syndrome?

A

cholesterol supplementation

60
Q

Describe the effects of a mutation in the mevalonate kinase gene.

A

though mevalonate kinase is pretty far along the pathway, a defect doesn’t cause as severe of problems because the accumulating intermediate (mevalonate) is water-soluble

61
Q

Under what conditions would you be able to reduce the risk of a heart attack to 0%?

A

if you were able to reduce blood [LDL] to under 55 mg/dL

62
Q

Draw out the pathway of the alternate fates of cholesterol biosynthetic intermediates.

A
63
Q

What are the top three cholesterol-producing tissues in the body? Keep in mind that this is separate from cholesterol content.

A

liver > adrenal > small intestine

Tissues (23 decks)

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