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BIOL 3421 - molecular biochem > lipid synthesis: cholesterol > Flashcards

lipid synthesis: cholesterol Flashcards

1
Q

list 5 things cholesterol is important for (showing that it’s not always a bad thing)

A
  • component of cell membranes
  • precursor to steroid hormones
  • helps make bile salts
  • helps synthesize NTs
  • helps synthesize vitamin D3
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2
Q

T or F: we can make our own cholesterol

A

true! we don’t actually require it in our diet

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3
Q

where does most cholesterol synthesis occur

A

in the liver

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4
Q

how many carbons is cholesterol

A

27

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5
Q

where do the 27C of cholesterol come from

A

all from acetyl-CoA

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6
Q

how many carbons is acetyl-coa

A

2

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7
Q

______ produce intermediates between acetate (acetyl-CoA) and cholesterol

A

isoprene units

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8
Q

how many carbons in one isoprene unit

A

5

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9
Q

how are isoprenes activated

A

by the addition of one or more P

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10
Q

in what three forms is cholesterol mostly exported from the liver

A

steroid hormones, bile acids, vitamin D

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11
Q

list the 4 basic steps of cholesterol synthesis

A
  1. make mevalonate from acetyl-CoAs
  2. make an activated isoprene unit from mevalonate
  3. condense 6 activated isoprenes together to make 30C linear squalene
  4. make squalene cyclical and remove a couple methyl groups to make cholesterol
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12
Q

what is the first step to making mevalonate

A

acetyl CoA + acetyl CoA = acetoacetyl-CoA
acetoacetyl-CoA + acetyl-CoA = HMG-CoA (6C)

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13
Q

once HMG-CoA is made from 3 acetyl-CoAs, how is mevalonate made

A

HMG-CoA is reduced to mevalonate (NADPH as the electron donor)

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14
Q

which step of mevalonate synthesis is the commitment step

A

the reduction of HMG-CoA to mevalonate

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15
Q

which enzyme reduces HMG-CoA to mevalonate (NADPH is the electron donor)

A

HMG-CoA reductase

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16
Q

once mevalonate is made, what is the next step in cholesterol synthesis

A

making activated isoprene units from mevalonate

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17
Q

describe how active isoprene units are made from mevalonate

A

3 phosphates from separate ATPs are transferred to mevalonate

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18
Q

T or F: when making isoprene units from mevalonate, the three needed phosphates come from one ATP

A

false! each phosphate comes from a DIFFERENT ATP

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19
Q

what is the next step in isoprene synthesis when we have mevalonate-P-P-P

A

the molecule is decarboxylated and one P leaves

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20
Q

how many carbons is mevalonate

A

6

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21
Q

after mevalonate-P-P-P is decarboxylated and one P has left, what molecule do we have

A

a 5C activated isoprene (5C-P-P)

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22
Q

during cholesterol synthesis, what is the next step once we have an activated isoprene (5C-P-P)

A

condense 6 isoprenes to make squalene

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23
Q

how many carbons is squalene

A

30

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24
Q

in squalene synthesis, in what configuration are the isoprenes attached to each other

A

head to tail

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25
Q

what is the “head” of the isoprene unit

A

the pyrophosphate end

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26
Q

what is the “tail” of the isoprene unit

A

the 5C unit

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27
Q

describe the events that occur when two isoprenes are condensed to form a 10C molecule

A

one of the two pyrophosphate sets is displaced

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28
Q

during isoprene condensation, what is the 10C-P-P intermediate called

A

geranyl pyrophosphate (10C-P-P)

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29
Q

describe the events that occur when the 10C-P-P (geranyl pyrophosphate) molecule is condensed with another 5C isoprene unit

A

one of the pyrophosphate sets is displaced = 15C-P-P molecule

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30
Q

during isoprene condensation, what is the 15C-P-P intermediate called

A

farnesyl pyrophosphate

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31
Q

during isoprene condensation, what is the next step once we have made 15C-P-P (farnesyl pyrophosphate)

A

we join to of those molecules together to get squalene
(15C-P-P + 15C-P-P)

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32
Q

during squalene synthesis, how are the two 15C-P-P molecules joined (what configuration)

A

head to head! (NOT head to tail)

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33
Q

what happens to the phosphates when 15C-P-P is added to 15C-P-P

A

all 4 phosphates are lost

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34
Q

T or F: squalene has 4 phosphates

A

false; it has no phosphates. All of them were lost during the head to head condensation of 15C-P-P + 15C-P-P

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35
Q

is squalene linear or circular

A

linear

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36
Q

is cholesterol linear or circular

A

circular

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37
Q

what still needs to be done to convert squalene to cholesterol (3)

A

close off the 4 rings, reduce the double bonds in the alkyl chain, add a hydroxyl

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38
Q

what is the first step of making cholesterol from squalene

A

a monooxygenase adds one oxygen of O2 to make an epoxide. The other oxygen gets reduced to water

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39
Q

during cholesterol synthesis from squalene, what occurs once an epoxide has been made

A

the epoxide can then be cyclized via a cyclase

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40
Q

during cholesterol synthesis from squalene, what molecule is made once the epoxide is cyclized via a cyclase

A

lanosterol

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41
Q

T or F: lanosterol is found in both plants and animals

A

false; lanosterol is in animals only

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42
Q

since plants lack lanosterol, describe what their cholesterol pathway looks like

A

the pathway will diverge before cyclization can occur

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43
Q

at what point in the squalene –> cholesterol pathway does it diverge between animals and plants? (ie which molecule is it)

A

squalene 2,3-epoxide

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44
Q

in the plant squalene -> cholesterol pathway, what are the products (instead of lanosterol)

A

stigmasterol and ergosterol

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45
Q

in the animal squalene -> cholesterol pathway, what happens once lanosterol has been produced

A

it’s then converted to cholesterol in 20+ minor steps that move around the methyl groups

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46
Q

are the derivatives of cholesterol more or less polar than cholesterol

A

more polar!

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47
Q

are the derivatives of cholesterol more or less hydrophobic than cholesterol

A

less hydrophobic!

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48
Q

list 4 less hydrophobic derivatives of cholesterol

A

hydroxysterols, bile salts, steroid hormones, vitamin D

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49
Q

list 1 derivative of cholesterol that is more hydrophobic than cholesterol

A

cholesteryl ester

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50
Q

what is a cholesteryl ester

A

a cholesterol bound to a FA

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51
Q

how many ATP were needed to make one cholesterol molecule

A

18

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52
Q

describe why 18 ATP were needed to make 1 cholesterol molecule

A

3 needed to make each mevalonate-P-P-P (which leads to one isoprene), but we need 6 isoprene = 3x6 = 18 total ATP

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53
Q

T or F: cholesterol is broken down in animal cells

A

false! it cannot be catabolized in animal cells!

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54
Q

since cholesterol cannot be broken down in animal cells, where does excess cholesterol go?

A

it must be excreted

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55
Q

which step of cholesterol synthesis is regulated

A

HMG-CoA –> mevalonate (the commitment step)

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56
Q

what hormone activates HMG-CoA reductase? how?

A

insulin. reversible phosphorylation

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57
Q

what hormone inactivates HMG-CoA reductase? how

A

glucagon. reversible phosphorylation

58
Q

other than insulin and glucagon, what enzyme regulates HMG-CoA reductase. how?

A

AMP kinase. reversible phosphorylation

59
Q

does AMP kinase activate or inactivate HMG-CoA reductase

A

inactivate

60
Q

when does AMP kinase inactivate HMG-CoA reductase? why?

A

when ATP levels are low. This is because cholesterol synthesis uses lots of ATP

61
Q

T or F: high blood cholesterol increases risk of heart attack and stroke

A

true

62
Q

____ are a common group of drugs that lower blood cholesterol levels

A

Statins

63
Q

describe how statins lower blood cholesterol levels. which step do they act at?

A

they inhibit HMG-CoA reductase by binding and blocking the active site during the HMG-CoA –> mevalonate step

64
Q

other then preventing cholesterol synthesis, what benefit can statins have

A

they encourage less tumor growth

65
Q

describe how statins can prevent tumor growth

A

RAS is a protein found overexpressed/overactive in tumors, and it’s attached to an isoprene derived lipid (15C-P-P). by taking statins, we get less isoprenes = less functional RAS = less tumor growth

66
Q

T or F: A negative feedback loop regulates HMG-CoA reductase gene expression based on dietary intake of cholesterol

A

true

67
Q

HMG-CoA reductase gene expression depends on which family of proteins

A

sterol regulatory element binding proteins (SREBPs)

68
Q

what does SREBP stand for

A

sterol regulatory element binding protein

69
Q

when first synthesized, where does SREBP embed

A

in the ER membrane

70
Q

describe the activities in the ER membrane when cholesterol levels are high

A

sterols bind to Insig and SREBP cleavage activating protein (SCAP) in the ER membrane. Sterol-bound Insig acts like an anchor and keeps SCAP-SREBP in the ER

71
Q

describe the activities in the ER membrane when cholesterol levels are low

A

sterols can no longer bind to Insig, so the anchor is degraded. SCAP then shuttles SREBP to the golgi membrane to be cleaved by proteases. A portion of the cleaved SREBP leaves the golgi into the nucleus to act as a TF to enhance gene expression of sterol synthesizing enzymes = increase in cholesterol synthesis

72
Q

in what form do cholesterol and cholesteryl esters travel through the blood

A

as lipoproteins

73
Q

what type of carrier proteins do lipoproteins have

A

apolipoproteins

74
Q

describe the structure of lipoproteins

A

they have carrier proteins (apolipoproteins) along with their huge stash of lipids + they have a single layer of outer phospholipids

75
Q

list the 4 classes of lipoproteins

A

chylomicrons, VLDL, LDL, HDL

76
Q

what is heavier: protein or lipid

A

protein

77
Q

if a lipoprotein has more lipid in regards to protein, does it have a high or low density

A

low density

78
Q

what are apolipoproteins recognized by in order for them to help target specific classes of lipoproteins to specific tissues

A

recognized by cell surface receptors

79
Q

list the 4 main pathways of lipoprotein movement

A

exogenous, enterhepatic, endogenous, reverse cholesterol transport pathway

80
Q

which lipoprotein is the least dense? it has the most of what type of molecule

A

chylomicrons = least dense. They have the most TAGs (lipids)

81
Q

briefly, what does the exogenous pathway do to chylomicrons

A

brings them from the small intestine to release free cholesterol in the liver

82
Q

where in the body are chylomicrons generated

A

cells of the small intestine

83
Q

where in the cells of the small intestine are chylomicrons generated

A

in the ER

84
Q

from the small intestine, where do chylomicrons go (exogenous pathway)

A

they enter the lymphatic system

85
Q

from the lymphatic system in the exogenous pathway, where do chylomicrons go

A

to the blood stream

86
Q

from the bloodstream, what do chylomicrons do (exogenous pathway) + where has the bloodstream taken them

A

the apolipoprotein portion activates lipases in the capillaries of adipose, heart, mammary tissue, and also skeletal muscles

87
Q

after apolipoproteins have activated lipases in adipose/heart/mammary/skeletal muscle tissues, what happens? (exogenous pathway)

A

free FAs are released from TAGs in these tissues

88
Q

in the exogenous pathway, once free FAs have been released from TAGs in the heart/adipose/mammary/skeletal muscle tissue, in what state is chylomicron in?

A

the chylomicron remnants are now depleted of TAGs, but they’re still carrying dietary cholesterol

89
Q

in the exogenous pathway, what happens to chylomicrons once they’re depleted of TAGs but still carry dietary cholesterol?

A

chylomicron remnants travel to the liver

90
Q

what happens to chylomicron remnants in the liver?

A

they’re endocytosed and degraded by lysosomes

91
Q

what is the result once chylomicrons are endocytosed and degraded by lysosomes in the liver?

A

dietary cholesterol is now free in the liver

92
Q

T or F: all the dietary cholesterol in the liver (from the exogenous pathway) will be used

A

false; some will be used by membranes/building derivatives, but some will be excess

93
Q

briefly, what does the enterohepatic pathway do

A

converts some liver cholesterol into bile salts in peroxisomes

94
Q

where are bile salts stored

A

gallbladder

95
Q

where will bile salts be secreted

A

into the small intestine

96
Q

what do bile salts do in the small intestine

A

they emulsify fats

97
Q

what does it mean to emulsify fats

A

to make the fats into smaller droplets

98
Q

T or F: emulsification involves the breaking of bonds

A

false; no bonds are broken, but the fats are made into smaller droplets

99
Q

after emulsifying fats, what are the two fates of bile salts

A

they can be reabsorbed into the liver or removed from the body with feces

100
Q

briefly, what is the purpose of the endogenous pathway

A

excess dietary FAs/cholesterol in the liver are packaged into TAGs or cholesteryl esters + put into VLDL (excess cholesterol in liver goes to other tissues to be stored)

101
Q

from the liver, where do VLDL go? (endogenous pathwat)

A

they travel through the bloodstream to muscle and adipose tissue

102
Q

what happens to VLDL in muscle/adipose tissue (endogenous pathway)

A

apolipoproteins stimulate lipoprotein lipase activity and free FAs are released into these tissues

103
Q

what happens to the density of VLDL when they lose some free FAs into muscle/adipose tissue (endogenous pathway)

A

it raises the density

104
Q

what happens to VLDL when the density increases (endogenous pathway)

A

VLDL –> LDL

105
Q

what do adipocytes do with the newly acquired free FAs from VLDL? (endogenous pathway)

A

they convert them to TAGs in lipid droplets for storage

106
Q

what do muscle cells do with the newly acquired free FAs from VLDL? (endogenous pathway)

A

they oxidize them immediately to produce energy (in a fast)

107
Q

each LDL has about ____ cholesteryl esters

A

1500

108
Q

each LDL has about ___ molecules of cholesterol

A

500

109
Q

in the endogenous pathway, what happens to LDL once it has converted from VLDL

A

it will now deposit cholesterol into tissues

110
Q

which cells have LDL receptors on their PM (3)

A

muscle, adipose, and macrophages

111
Q

for the cells that have LDL receptors on their PM, what will they do to LDL? (endogenous pathway)

A

they’re mediate cholesterol uptake from LDL, leaving LDL without cholesterol (note: it’s already also depleted of FA)

112
Q

after LDL has dropped off its cholesterol into tissues, what happens (endogenous pathway)

A

it goes back to the liver

113
Q

what happens to depleted LDL when it arrives at the liver (endogenous pathway)

A

LDL receptors on hepatocyte PM mediate reuptake of the entire LDL

114
Q

what part of LDL is recognized by liver PM LDL receptors (endogenous pathway)

A

ApoB protein

115
Q

describe the steps of receptor mediated endocytosis into a liver cell

A

LDL binds to a receptor which initiates endocytosis into the liver cell. LDL and its receptor enters the cell in an endosome, the portions of the endosome containing the receptor bud off and return to the PM. The rest of the endosome fuses with the lysosome where enzymes hydrolyze cholesteryl esters to release cholesterol + free FAs into the cytosol. ApoB is also degraded to amino acids

116
Q

in what structure does an LDL and its receptor enter a cell

A

an endosome

117
Q

once an LDL and its receptor have entered a cell in an endosome, what does that endosome fuse with

A

a lysosome

118
Q

once an endosome containing LDL and its receptor have fused with a lysosome, what happens?

A

enzymes hydrolyze cholesteryl esters to release cholesterol and free FAs into the cytosol

119
Q

what is ApoB degraded into

A

amino acids

120
Q

what mutation do people with hypercholesterolemia have

A

mutations in the LDL receptor that prevents normal uptake of LDL particles in the liver

121
Q

results of having hypercholesterolemia?

A

high blood cholesterol levels, higher risk of developing atherosclerosis plaques, cholesterol deposits in weird places (elbows, knees, cornea), coronary events in childhood

122
Q

briefly, what does the reverse cholesterol pathway do

A

removes excess cholesterol from peripheral tissues and brings them to the liver

123
Q

in the reverse cholesterol pathway, where do HDL originate?

A

the liver

124
Q

in the reverse cholesterol pathway, describe the composition of the HDL particles that originate in the liver (think lipid and protein content)

A

HDL in the liver are protein rich. They have little cholesterol, no cholesteryl esters, and no TAGs

125
Q

in the reverse cholesterol pathway, what enzyme do HDL contain

A

LCAT

126
Q

in the reverse cholesterol pathway, what does LCAT do

A

generates cholesteryl esters from cholesterol and phosphatidylcholine

127
Q

in the reverse cholesterol pathway, where on HDL is LCAT located

A

surface

128
Q

in the reverse cholesterol pathway, where in the body would LCAT be working

A

in the blood + peripheral tissues

129
Q

T or F: in the reverse cholesterol pathway, HDL can also pick up cholesteryl esters from peripheral tissues (meaning it doesn’t only rely on LCAT)

A

true

130
Q

in the reverse cholesterol pathway, describe how HDL picks up cholesteryl esters from peripheral tissues

A

Picks it up from macrophages

131
Q

in the reverse cholesterol pathway, where does HDL take all the excess cholesterol it’s picked up from peripheral tissues + LCAT activity

A

to the liver

132
Q

in the reverse cholesterol pathway, describe what happens upon HDL returning to the liver (how does it drop off its cholesterol)

A

HDL apolipoproteins will bind to receptors on the PM, but the whole particle is NOT endocytosed. Instead, cholesterol and other lipids will selectively enter the liver

133
Q

T or F: in the reverse cholesterol pathway, the entire HDL is endocytosed into the liver

A

false; cholesterol and other lipids will selectively enter

134
Q

in the reverse cholesterol pathway, what happens to HDL once it’s returned the cholesterol to the liver

A

HDL dissociates from liver cells and can recirculate in the blood to collect more cholesteryl esters

135
Q

what are plaques? what do they cause?

A

they’re accumulations of cholesterol that obstruct blood vessels and cause atherosclerosis, or lead to heart attack/stroke

136
Q

how does HDL affect plaques

A

depleted HDL can pick up cholesterol at nascent plaques and return it to the liver (this depletes plaques)

137
Q

are LDL good or bad when it comes to plaque formation

A

bad! they can undergo a few steps that lead to plaque formation

138
Q

describe the events that LDL can undergo that lead to plaque formation

A

LDL can adhere to the ECM of epithelial cells that line arteries. WBCs will be attracted to these regions and uptake mass amounts of LDL until they become foam cells. These foam cells will eventually undergo apoptosis, and the remnants will contribute to a developing plaque

139
Q

is LCAT + reverse cholesterol transport good or bad when it comes to plaques? explain

A

good! they can pick up some of the cholesterol in a growing plaque and return it to the liver, slowing plaque growth

140
Q

list some things that might increase your HDL:LDL ratio

A

taking a statin, eating omega 3’s, maintaining healthy weight, exercise, stopping smoking, eating foods with red/purple pigments, taking niacin (B3) supplements

BIOL 3421 - molecular biochem (20 decks)

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