Cholesterol Biosynthesis Flashcards

1
Q

Example of bad cholesterol

A

LDL (Low density lipoprotein)

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2
Q

Composition of a cholesterol molecule (2 parts)

A
Steroid nucleus (4 fused rings)
Hydrocarbon tail
(possible long chain FA at C3 if esterified)
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3
Q

What makes a cholesterol ester

A

A long chain FA added to the A ring at Carbon #3

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4
Q

Cholesterol esters are highly (hydrophilic/phobic)

A

Hydrophobic

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5
Q

% of cholesterols that are esterified

A

70%

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6
Q

_________ are in the interior of the lipoproteins, while ________ is on the surface

A

Cholesterol esters; free cholesterol

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7
Q

Roles of cholesterol

A
Membrane composition
Signaling
Bile acids
Steroid hormones
Vitamin D
Embryo formation
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8
Q

Greatest synthetic site of cholesterol

A

Liver (80%)

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9
Q

Rate-limiting step in cholesterol synthesis

A

HMG CoA reductase

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10
Q

HMG CoA reductase activity is inhibited by ____________

A

free, non-esterified cholesterol

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11
Q

Insulin (inhibits/stimulates) gene expression of HMG CoA reductase

A

Stimulates (promotes storage as cholesterol)

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12
Q

Class of drugs that are structural analogs of HMG CoA; bind and competitively inhibit enzyme

A

Statin drugs

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13
Q

HMG CoA reductase sits on what membrane?

A

Endoplasmic Reticulum

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14
Q

Cholesterol derivative involved in oxidative phosphorylation

A

Coenzyme Q10

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15
Q

Cholesterol derivative involved in synthesis of glycoproteins

A

Dolichol phosphate

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16
Q

Cholesterol derivatives involved in signal transduction

A

Rho and Ras

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17
Q

In cholesterol-depleted cells, this protein binds to SREBPs and mediates their transport from the ER to the Golgi apparatus. The SREBPs are then proteolytically cleaved and stimulate sterol biosynthesis.

A

SCAP

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18
Q

High cholesterol can create _______, which can inhibit SCAP and prevent cholesterol biosynthesis via HMG CoA

A

Oxysterols

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19
Q

LDL receptors are down-regulated by…

A

free cholesterol

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20
Q

Role of LDL

A

provide cholesterol to peripheral tissue

return it to the liver

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21
Q

LDL receptors

A

Apo B100

Apo E

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22
Q

Enzyme that esterifies cholesterols for storage

A

ACAT

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23
Q

A diet high in saturated fats can have what enzymatic effects?

A
Inhibit ACAT (can only use unsaturated)
Reduced LDL
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24
Q

A diet low in fiber can have what enzymatic effects?

A

Fiber binds bile acids in intestine, increasing clearance.

Low fiber means increased bile acids circulating, inhibiting 7a hydroxylase

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25
Q

Rate limiting step in bile acid synthesis

A

7a-hydroxylation

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26
Q

Primary bile acids made by liver

A

Cholic acid

Chenodeoxycholic acids

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27
Q

Why are bile acids good emulsifiers

A

have polar and nonpolar portions

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28
Q

Only significant mechanism for eliminating cholesterol from the body

A

Conversion into bile

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29
Q

What regulates 7a-hydroxylase activity?

A
cholesterol (activates)
bile acids (inhibited)
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30
Q

% of bile acids that are reabsorbed in enterohepatic circulation

A

99%

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31
Q

Drug that inhibits cholesterol absorption in small intestine

A

Etzetimibe

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32
Q

Drug that binds bile acid in intestine

A

Cholestyramine

33
Q

Transport “vehicle” for TGs, PLs, cholesterol and CEs in conjuction with apoproteins

A

Lipoproteins

34
Q

Cholesterol esters are located in the (core/surface) of lipoproteins

A

Core

35
Q

Pattern of lipoproteins in order of least to most dense

A

Chylomicrons–>VLDL–>LDL—>HDL

36
Q

The more dense the lipoprotein, the (bigger/smaller) and (more/less) triglycerides

A

Smaller; less TGs

37
Q

What hormone helps with production and unloading of cholesterol at tissues

A

Insulin

38
Q

Apoprotein that activates lipoprotein lipase (LPL); offloading at peripheral tissue

A

Apo C

39
Q

Apoprotein involved in binding of HDL to peripheral tissues and activates LCAT (forms esters); also activates ABC1, which is responsible for 50% of cholesterol efflux from peripheral tissue

A

Apo A

40
Q

Apoproteins on chylomicrons after formation in intestine

A

Apo A

41
Q

Apoprotein involved in binding of LDL to liver receptors

A

Apo B-100

42
Q

Apoprotein involved in binding chylomicrons, VLDL and HDL to liver after TGs have been removed

A

Apo E

43
Q

Apoproteins involved in binding of IDL to the liver

A

Apo E plus Apo B-100

44
Q

Enzyme located on endothelial surfaces of capillaries (especially adipose tissue); required for TG hydrolysis from chylomicrons and VLDL; activated by apo C and insulin

A

Lipoprotein Lipase

45
Q

Enzyme located on endothelial surfaces of capillaries (liver); used in conversion of VLDL and IDL to LDL

A

Hepatic Lipase

46
Q

______ is a lipoprotein that is an important acceptor and donor of apoproteins

A

HDL

47
Q

HDL gives what to chylomicrons so they can deposit TG and be recycled

A

Apo C
Apo E
Cholesterol esters

48
Q

Half-time of exogenous pathway of chylomicrons

A

very short (minutes)

49
Q

After VLDL has TG removed and apoC lost to HDL, it becomes…

A

IDL (remnant particle)

50
Q

Two classes of IDL

A

rich in apoE: bind to liver and is destroyed (rapid= hours)

little apoE: converted to LDL, loses cholesterol to tissues and binds to liver (slowly= days)

51
Q

lipoprotein that transports cholesterol from peripheral tissue to liver

A

HDL

52
Q

enzyme that catalyzes esterification of cholesterol associated with HDL; activated by Apo A

A

LCAT

53
Q

protein that transfers the cholesterol esters from HDL to VLDL, IDL, and LDL; represents main mechanism of cholesterol delivery to liver

A

Cholesterol Ester Transfer Protein (CETP)

54
Q

protein that transfers TGs and phospholipids from VLDL, LDL and IDL to HDL

A

Phospholipid Transfer protein (PLTP)

55
Q

transport protein responsible for 50% of cholesterol efflux from peripheral tissues to HDL; activated by Apo A

A

ABC1

56
Q

Nascent HDL (empty lipid bilayer) made by the liver has what apoproteins

A

Apo A and Apo E

57
Q

What are the intermediates of cholesterol?

A
  1. geranyl diphosphate (C10)

2. Farnesyl diphosphate (C15)

58
Q

What can farnesyl diphosphate turn into?

A

geranylgeranyl diphosphate (C20)

59
Q

What can geranylgeranyl diphosphate become that is involved in oxidative phosphorylation?

A

Coenzyme Q10 (ubiquinone)

60
Q

What can geranylgeranyl diphosphate become that is involved in signal transduction?

A

geranylgeranlyated proteins (Rho)

61
Q

What can farnesyl diphosphate become that is involved in signal transduction?

A

farnesylated proteins (Ras)

62
Q

What can farnesyl diphosphate become that is involved in synthesis of complex glycoproteins?

A

dolichol phosphate

63
Q

How many carbons does mevalonate have?

A

C6

64
Q

How many carbons does cholesterol have?

A

C27

65
Q

What enzyme metabolizes HMGCoA during fasting state for energy?

A

HMGCoA Lyase (in mitochondria) produces acetyl coa & acetoacetate

66
Q

What is SREBP-2 and SCAP?

A

SREBP-2 is a transcription factor that regulates the gene expression of HMGCoA synthase, reductase, and LDLR.

SCAP is a protein that binds and transports SREBP-2 from ER to golgi.

67
Q

What happens to SREBP-2 in Golgi?

A

SREBP-2 gets cleaved by protease and gets activated. Then it moves to the nucleus to regulate HMGCoA synthase, reductase, and LDLR at the transcription level.

68
Q

What up-regulates HMGCoA reductase expression?

A

Insulin (during fed state)

69
Q

What down-regulates HMGCoA reductase expression?

A

Intracellular (free, non-esterified) cholesterol by producing oxysterols that inhibit SCAP –> inhibition of SREBP-2 transcription factor.

70
Q

A diet high in saturated fats can have what effects?

A
  1. Inhibit ACAT (it only uses PUFAs to esterify cholesterol)
  2. Increase plasma LDL (SF reduces membrane fluidity since it has no double bond –> reduced clustering and uptake of LDLR)
71
Q

Primary bile acids made by liver are

A
  1. Cholic acid (has glycine)

2. Chenodeoxycholic acid

72
Q

What is the rate-limiting step of bile acid synthesis?

A

7a-hydroxylation

73
Q

What are the bile acids/salts made when primary bile acids get further metabolized in the intestine?

A
  1. Deoxycholic acid

2. Lithocholic acid

74
Q

What are the primary functions of bile acids (3)?

A
  1. fat digestion
  2. absorption of fat-soluble vitamins
  3. prevent the precipitation of free cholesterol out of solution in the gall bladder
75
Q

What enzyme is located on the endothelial surface of blood capillaries adjacent to tissues capable of using fats and is required for TG hydrolysis?

A

Lipoprotein lipase (LPL)

*activated by insulin

76
Q

What enzyme is located on the endothelial surface of blood capillaries adjacent to liver and is required for TG hydrolysis?

A

Hepatic lipase (HL)

*NOT regulated by insulin

77
Q

what apoprotein is needed to activate LPL?

A

apoprotein C

78
Q

what apoprotein is needed for chylomicron to bind to the liver?

A

Apo E and ApoB-100