Week 12 - Unit 3 Flashcards

1
Q

Cholesterol can come from both the diet and is synthesized in the body. True or false?

A

True

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2
Q

True or False:

the majority of cholesterol in the body is form dietary sources.

A

False- most is from endogenous synthesis

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3
Q

Cholesterol is used as a membrane sterol and is the precursor for all ______ ______.

A

Steroid hormones

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4
Q

Cholesterol is transported in ______ in the body.

A

Lipoproteins

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5
Q

Dietary cholesterol is transported in ______.

A

chylomicrons

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6
Q

Cholesterol is synthesized in the _____ (but most tissues can synthesis it if needed) and packaged into _____ particles.

A

Liver (primary)

VLDL

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7
Q

VLDL particles mature to ______ particles, that are taken up by cells via the ____ ______.

A

LDL

LDL receptor

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8
Q

Cholesterol is transported from peripheral tissues back to the liver via _____ particles.

A

HDL

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9
Q

What three levels is cholesterol synthesis regulated at ?

A

Phosphorylation
Transcription
Feed-back inhibition

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10
Q

Statins are cholesterol reducing drugs that target the regulatory enzyme ______.

A

HMG CoA reductase

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11
Q

Cholesterol has a ring structure with a _____ group on the ___ carbon, this allows it to be amphipathic (can insert into membrane).

A

Hydroxyl

3 carbon

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12
Q

Cholesterol is a ______ (shape)molecule and can influence the _____ of the cell membrane when inserted.

A

planar

fluidity

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13
Q

Approx how much cholesterol in the body is in the free form ?

A

1/3

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14
Q

What happens to the other 2/3 of the cholesterol in the body that is not in free form?

A

It is Esterified

-FA added with ester bond to the OH on the 3 carbon of Cholesterol

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15
Q

What does esterification of cholesterol do ?

A

keeps the cholesterol within the cell and out of the cell membrane (means of storage)

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16
Q

Creation of Cholesterol needs a lot of energy and is provided in the form of _____.

A

NADPH

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17
Q

Synthesis of Cholesterol starts with condensation of 2 _____ to make ______.

A

Acetyl CoA (CoAsh is released)

Acetoacetyl CoA

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18
Q

What is the intermediate generated in the first steps of cholesterol synthesis?

A

Mevalonate

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19
Q

In synthesis of Cholesterol, what does Acetoacetyl CoA condense combine with to make beta-hydroxy-beta-methyl glutaryl CoA (HMG-CoA)

A

Acetyl CoA (CoASH is released)

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20
Q

Where does Cholesterol synthesis take place?

Where does ketone synthesis take place?

A

Cytosol

Mitochondria

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21
Q

What is the regulatory enzyme for Cholesterol synthesis in the first steps involving Acetyl CoA to form intermediate Mevalonate?

A

HMG-CoA reductase

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22
Q

Where is HMG-CoA reductase?

describe its physical features?

A

ER membrane

8 Transmembrane domains

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23
Q

What does HMG-CoA reductase in the ER membrane use for energy?

A

2NADPH+2H

and release of CoASh

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24
Q

What level is HMG-CoA reductase regulated at ?

A

Transcriptional level (highly regulated)

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25
Q

When Cholesterol levels are high , it binds ______ and the receptor ______ that is next to the one it binds forming a transcription factor family complex in the ER

A

SCAP (sterol response element binding protein cleavage activating protein)

SREBP (sterol response element binding protein)

-Transcription factor family complex

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26
Q

As Cholesterol levels drop, it is released from SCAP in the ER, and SCAP and SREBP move to the membrane of _______.

A

Golgi

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27
Q

In the golgi, after the transcription factors have moved into the membrane during low cholesterol levels, there is a cleavage reaction that releases the _________ from _____ that is facilitated by ______ _______.

A

DNA-binding domain

SREBP

2 Proteases (S1P and S2P)

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28
Q

The DNA binding domain for SCAP+SREBP will translocate to the _______ once cleaved from the golgi.

A

nucleus

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29
Q

Once in the nucleus, the SCAP+SREBP DNA-binding domain will bind the ________ ______ ______.
This will then ……..

A

Sterol response element (Regulatory element) SRE

then regulate gene transcription to increase production of HMG-CoA reductase in the cell when Cholesterol levels are low

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30
Q

HMG-CoA Reductase is also impacted/regulated by high levels of _____ in the cell.

A

Sterols

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31
Q

High levels of Sterols will target ______ ______ in the ER membrane for proteolysis and degradation in the cell (decreases the synthesis of cholesterol).

A

HMG-CoA reductase (control by degredation)

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32
Q

HMG-CoA reductase is also controlled by phosphorylation, under high levels of insuling, the _______ is activated and will _______ it making it active.

A

Phosphatase

dephosphorylate

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33
Q

What will inactivate the HMG-CoA reductase (through covalent modification)?

A

High levels of :
AMP, Glucagon, Sterols
-all activate the AMP-activated protein kinase to phosphorylate and inactivate the HMG-CoA reductase

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34
Q

From the starting point of Mevalonate (cholesterol synthesis intermediate), there are _____ reactions adding _____ _____ groups.

A

3

3 phosphate groups

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35
Q

What is the purpose of the phosphate transfers (adding 3 groups) to mevalonate?

A

to activate Carbon 5 and Carbon 3

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36
Q

The phosphate group from Carbon 3 and the Carbonyl group from the end are removed to create a ______ ______ . This intermediate that is created will be the first of two necessary Isoprenes .

A

Double bond

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37
Q

What is the first necessary Isoprene created called how is it made?

A

1 Phosphate group and CO2 removed from :
3-phospho 5-pyrophosphate mevalonate

Name: Isopentenyl pyrophosphate (5 C) - synthetic precursor for cholesterol synthesis

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38
Q

Isopentenyl pyrophosphate is isomerized to __________

A

Dimethylallyl pyrophosphate (5C) (synthetic precursor for cholesterol synthesis)

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39
Q

What is the first step involving the two precursors to cholesterol?

A

condensation of:
Dimethylallyl pyrophosphate
Isopentenyl pyrophosphate
(release of 2 Pi and there is a total 2 Pi left on the new compound)

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40
Q

What is the new compound created when Demethylallyl pyrophosphate and Isopentenyl pyrophosphate are condensed and 2 Pi is released?

A

Geranyl pyrophosphate (10C- intermediate)

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41
Q

What is added to the Geranyl pyrophosphate (10C) to make the 15C substance in Cholesterol synthesis?

A
Isopentenyl pyrophosphate (5C)
-one Pi is released
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42
Q

What is the 15C intermediate in Cholesterol synthesis called after Isopentenyl pyrophosphate is added to Geranyl pyrophosphate ?

A

Farnesyl pyrophosphate

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43
Q

What is the next reaction after Farnesyl pyrophosphate (15C) is created?

A

2 Farnesyl pyrophosphates are condensed to create:
Squalene (30C intermediate)
-2 PPi released
-NADPH is used and leaves NADP+

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44
Q

Why are Geranyl pyrophosphate and Farnesyl pyrophosphate important for reasons besides cholesterol synthesis?

A

They can both be used to attach to proteins to change their function (similar to phosphorylation)

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45
Q

What happens to the 30C Squalene molecule in cholesterol synthesis?

A

Oxygenated by enzyme:
Squalene monooxygenase
-NADPH is used and NADP+ released
-O2 used and H2O released

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46
Q

What is created when Squalene (30C-intermediate) is acted on by Squalene monooxygenase, what is the product called? what feature does it have?

A

Squalene 2,3 epoxide

Epoxide ring (open ring with oxygen hanging off end)

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47
Q

The opening of the epoxide ring on Squalene 2,3 epoxide will facilitate cyclization into the first cyclic-intermediate called _______.

A

Lanosterol

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48
Q

What is Lanosterol used for ?

A

first foundational cyclic-intermediate

used to create Cholesterol (through many reactions)

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49
Q

Once synthesized in the cytosol, Cholesterol has many fates, one fate is the esterfication into Cholesterol Ester by ……..
what is the enzyme that carries this out ?

A

Fatty Acyl-CoA is added to Hydroxyl group (CoASH released)

Enzyme: ACAT (Acetyl CoA acyl-transferase)

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50
Q

Cholesterol ester is more ______ than regular cholesterol and are packaged into VLDL particles for transport to peripheral tissues.

A

Hydrophobic

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51
Q

In the synthesis of Cholesterol (hepatic) to Bile salts, the first step is the conversion of Cholesterol to what compound?

A

7-Alpha Hydroxycholesterol

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52
Q

What is added to a Carbon on Cholesterol to make 7-alpha-Hydroxycholesterol?

A

Hydroxyl group added to 7 carbon

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53
Q

What is the enzyme that will convert Cholesterol to 7alpha-hydroxycholesterol ?
what can inhibit the enzyme?

A

7-alpha hydroxylase (regulatory enzyme for pathway)

high levels of bile salts

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54
Q

When 7alpha-hydroxylase acts on Cholesterol, what will it need to make 7aplha-Hydroxycholesterol?

A

O2 + H+ (to provide the O, and then H2O is released)
NADPH reduces Cytochrome P450(Fe3+) to Cytochrome P450 (Fe2+) that can donate reduce the Cholesterol and donate the H needed to add an OH to cholesterol at the 7 carbon

55
Q

The series of reductions, hydroxylation, and conversion of hydroxyls to Alpha of 7Alpha-Hydroxycholesterol will produce what two primary compounds?

A

Chenodeoxycholic acid (has 2 OH- groups)

Cholic Acid (has 3 OH- groups-additional on 12C)

—-Double bond in Beta ring has been reduced (gone) in both structures

56
Q

The side chains of Chenodeoxycholic acid and Cholic acid are show as ionized (COO-) because the pKA is _____. So at a pH of ____ which is the pH in small intestine, 50% will be ionized and 50% will be protonated (example bile acid (ionized) vs bile salt)

A

6

6

57
Q

Which form of Chenodeoxycholic Acid and Cholic Acid is more effective as a detergent?

A

the Ionized form (COO-) is more effective vs. the protonated form

58
Q

To facilitate keeping the side chain of Bile Acids ionized, we can _________ bile acids with other compounds to ______ the pka of the side chain.

A

conjugate

reduce

59
Q

What are the two main compounds that can be added to Cholic acid side chain (COO-) to reduce the pka of the side chain?

A

Taurine and Glycine

60
Q

What is the name of the compound when Taurine is added to Cholic acid and what is the pka?

A

Taurocholic Acid

pKa = 2 (would be almost totally ionized at pKa 6 in intestine)

61
Q

What is the name of the compound when Glycine is added to Cholic acid and what is the pKa?

A

Glycocholic acid

pKa = 4 (would be almost totally ionized at pKa 6 in intestine)

62
Q

Lower pKa of the Bile acid molecules will _______ soluability and increase the _______ of fats during digestion.

A

increase

emulsification

63
Q

Less than _____ of Bile salts are secreted in feces. They are considered secondary bile salts that are ______ and _______ by bacteria in gut.

A

5%

Deconjugate
Dehydroxylate
reduces solubility and makes difficult to be absorbed

64
Q

What are the primary bile salts that are reabsorbed?

A
  1. Cholic acid

2. Chenodeoxycholic acid

65
Q

What are the secondary bile salts (removal of OH from 7 Carbon in both and less soluble) that are less likely to be reabsorbed?

A
  1. Deoxycholic acid (OH removed on 7 C)

2. Lithocholic acid (OH removed on 7 and 12 C)

66
Q

The secondary bile salts are mostly excreted in feces, and the ones that are recycled are not ________ but can be _________ to increase the solubility.

A

rehydroxylated (on Carbons)

Re-conjugated

67
Q

HMGCoA reductase activity would be reduced if SREBP is bound to SCAP in the ER. True or False?

A

True - associated with high cholesterol so transcription is reduced

68
Q

HMGCoA reductase activity would be reduced if elevated levels of sterols are in the cell. True or False?

A

True - keep activity low of enzyme, target the enzyme for degradation when sterols are high in cell

69
Q

HMGCoA reductase activity would be reduced if it is phosphorylated by AMPK (AMP-kinase).
True or False?

A

True - only active if dephosphorylated

70
Q

HMGCoA reductase activity would be reduced if there are elevated levels of insulin. True or False?

A

False- insulin will activate the phosphatase and increase the activity of the dephosphorylated HMG-CoA reductase

71
Q

What are the 4 main transporters of Cholesterol in the body?

A

Chylomicrons
VLDL to IDL
LDL
HDL

72
Q

What Apoproteins are associated with chylomicrons?

What happens after interaction with HDL?

A
  • ApoB48 (marker)
  • receive ApoCII and ApoE from interaction with HDL
  • Hydrolyzes to FA+Glycerol
73
Q

How is the Chylomicron recycled?

A

turns into Chylomicron remnant

  • ApoE on the chylomicron will bind to ApoE receptor on Liver to uptake it and recycle
74
Q

VLDL will primarily carry newly synthesized _____ and ______ (less) . The former is packaged into ___.

A

Fatty Acids (highest percent) and Cholesterol

TriacylGlycerols

75
Q

What Apoproteins is VLDL associated with

A

ApoB100 (marker)

-interact with HDL - receive ApoCII and ApoE

76
Q

What Apoprotein interacts with Lipoprotein lipase so FA can be freed and taken up by muscles and adipose?

A

ApoCII on the chylomicrons and VLDL

77
Q

When VLDL reduces it ____ content it will mature into ______ .

A

Triacylglycerol

LDL

78
Q

The LDL has a higher content of ______ than VLDL.

A

Cholesterol (up to 40 to 50%)

79
Q

LDL is taken up by ______ ______ and is a way of transporting cholesterol from liver to tissues.

A

peripheral tissues

80
Q

HDL are secreted as _____ lipoproteins from the liver, and their role is to interact with peripheral tissue and move _______ from tissue back to the liver.

A

Nascent

Cholesterol

81
Q

What is name for HDL (High density lipoproteins) function?

A

Reverse Cholesterol transport

82
Q

List the size of the Lipoproteins from largest to smallest?

A
Chylomicrons
Chylomicron remnant
VLDL
IDL
LDL
HDL
83
Q

Once VLDL has lost a large proportion of its TG, it is called an _____.

A

IDL (Intermediary Density Lipoprotein)

84
Q

The VLDL will mature into IDL and go back to liver and is taken up via interaction with ______on IDL and the ______receptor on Liver

A

ApoE

85
Q

The IDL can mature further into ______ through interaction with _________ in the blood.

A

LDL

HTGL ( Hepatic TriacylGlycerol Lipase) - lipase in the capillary walls - similar to LPL

86
Q

The removal of more _____ by ______ on the IDL particles results in the maturation of the particle into _____.

A

TG

Hepatic Triacylglycerol lipase (HTGL)

LDL

87
Q

LDL can be taken up by receptors on ____ and _____ tissue. This is how cholesterol is delivered to tissues in general.

A

liver

peripheral

88
Q

LDL has the apoprotein ______ that is characteristic of it.

A

ApoB100

89
Q

Excess LDL in pathological conditions will be _____ and will damage the vascular endothelial cells generating _________ ______ through the synthesis of foam cells.

A

oxidized

sclerotic plaque

90
Q

LDL with apoB100 (primarily cholesterol ester) , is taken up by peripheral tissue through ________ _____ ______ .

A

Receptor-mediated endocytosis - vesicle pinches off and entire LDL and receptor are in the endosome in cell

91
Q

The Receptor is _______ back to cell surface and the rest of the LDL core in the endosome is (cholesterol esters) is digested by _______ into what 3 things?

A

Recycled

Lysosomes

AA, FA, cholesterol

92
Q

The receptor mediated endocytosis of LDL will be a way to regulate ________ ______ of cholesterol by increasing levels in the ER membrane of cells and binding the transcription factor complex to stop transcription.

A

endogenous synthesis

93
Q

What three things will increasing levels of Cholesterol (sterols) do to HMG-CoA reductase when in the cell?

A
  1. Bind to the Transcription factor in ER (SCAP-SREBP) stopping endogenous transcription
  2. Increase HMG-CoA reductase degredation (proteolysis)
  3. Phosphorylate and inactivate HMG-CoA Reductase by increasing the activity of AMP-activated protein kinase
94
Q

There are many characterized mutations in the LDL receptor gene including what sections: (6)

A
  1. Promoter
  2. Ligand binding
  3. EGF precursor homology domain
  4. Glycosylation regions
  5. Membrane domain
  6. Cytoplasmic domain
95
Q

Many of the mutations in the LDL receptor gene cause what ?

A

Cholesterol to be elevated and pathological Hypercholesteremia in various family types

96
Q

In the comparison lipid panels:
If patient A has 420mg Cholesterol and 158mg TG
If patient A has 314mg Cholesterol and 295 mg TG
What do they have?

A

A has hypercholesterol only -

B has Metabolic syndrome

97
Q

If a patient has high Triacylglycerols, what is that reflective of ?

A

chylomicrons n/a (fasting labwork)- and cleared rapidly so rare to cause disturbance in TG levels

only levels of circulating VLDL

98
Q

If a patient has high Cholesterol level, what is this reflective of ?

A

elevated LDL particles

chylomicrons n/a in fasting labwork

99
Q

What three ways can HDL originate?

A
  1. From liver as nascent particles
  2. Budding off of VLDL or chylomicrons
  3. Accumulation of phospholipids around an ApoA protein
    (somewhat empty sack)
100
Q

HDL contain very ______ levels of TG and Cholesterol.

A

Low

101
Q

HDL moves ________ from _______rich cells back to the liver. HDL particles gain their contents from the _______ tissues.

A

cholesterol
Cholesterol

peripheral

102
Q

HDL can exchange ______ and ______ with other lipoproteins.

A

Apoproteins

Lipids

103
Q

HDL contains apoproteins _____ ______ , and ______. And have a ______ layer phospholipid membrane.

A

ApoA 1 and 2 (characterizing element)
ApoCII
ApoE

Mono

104
Q

One of the first roles of HDL is the transfer of ______ and ______ onto the Chylomicron and VLDL particles.

A

ApoCII (activates Lipoprotein lipase)

ApoE (required for re-uptake by the liver)

105
Q

When HDL particles encounter tissues/cells with high levels of cholesterol, you will have cholesterol _______ from that cell into the HDL particle.

A

Efflux

106
Q

The movement of cholesterol from the encountered tissues/cells into HDL is facilitated by the _______

A

ABCA transporters
- ATP binding cassette proteins - use ATP hydrolysis to move cholesterol from inner leaflet of membrane to outer leaflet of membrane where it can be moved into HDL particle

107
Q

Once the cholesterol has been picked up by the HDL particle from tissues, it must be _______ in order for the HDL particle to retain it inside its membrane.

A

Esterified

108
Q

The esterification of the Cholesterol in the HDL particle is performed by the enzyme ______

A

LCAT (lecithin cholesterol acyltranferase)
-similar to enzyme ACAT that is found inside the cell and performs the same action in the cell to esterify it to keep it inside the cell

109
Q

The reaction by LCAT (lecithin cholesterol acyltransferase) is the removal what from Lecithin?

Placed where on the Cholesterol?

A

Fatty acid from C2 Carbon from Lecithin

Placed on Hydroxyl group on 3C of Cholesterol (end cap
makes cholesterol Ester)

110
Q

What is Lecithin transformed into once LCAT (lecithin cholesterol acyltransferase) acts upon it to transfer a FA group to Cholesterol?

A

Lysolecithin

111
Q

Once Cholesterol is esterified within the HDL particle and is in circulation, the other function is the transfer of ______ from HDL to ______. This is a means by which the TG can be transferred to HDL and Cholesterol Ester can be transferred to _____.

A

lipids

VLDL

VLDL

112
Q

Transfer of Cholesterol ester from HDL to VLDL and the transfer of Triacylglycerols from VLDL to HDL is performed by the enzyme _______.

A

CETP (Cholesterol ester transferase protein)
-means of delivering cholesterol in higher concentrations back to the liver via the VLDL particle (first has to be matured to IDL and LDL then goes to liver)

113
Q

HDL can be taken up by the liver and is done by the _______ receptor also know as the _____ receptor.

A

Scavenger receptor

SR1 receptor

114
Q

Cholesterol is the precursor for ____ classes of ______.

A

5

Hormones

115
Q

What are the 5 classes that cholesterol is the precursor for (hormones)?

A
  1. Glucocorticoids
  2. Mineralcorticoids
  3. Androgens
  4. Estrogens
  5. Progestogens
116
Q

Hormones made from Cholesterol are hydrophobic and usually bound by _______ to travel through the blood.. Or to a specific carrier protein.

A

Albumin

117
Q

Hormones made from cholesterol will either bind to cytosolic receptors or receptors in then nucleus, but in either case the receptors will travel and bind to DNA and regulate _______ ________.

A

gene transcription

118
Q

Synthesis of Cortisol takes place in the _______ _____. It is initiated by the interaction of _______ binding ________.

A

Adrenal Cortex

ACTH …binding….G protein coupled receptor

119
Q

In the synthesis of cortisol, the ______ have previously come into the cells and deposited Cholesterol ester.

A

LDL

120
Q

The increasing cAMP activate _________ which then activates a ______ that cleaves Cholesterol into its free form away from the Cholesterol ester form.

A

Protein Kinase A

Lipase

121
Q

The cholesterol once cleaved from its ester form, under goes a series of reactions in ____ and _____ and creates ______ that can then diffuse out of the cell.

A

Mitochondria

Endoplasmic Reticulum

Cortisol (will bind with albumin to circulate)

122
Q

What 4 things can all contribute to an inflammatory state of the vascluar endothelium and lead to formation of a fatty streak ? (athlerosclerosis)

A
  1. Elevated LDL or reduced HDL
  2. Cigarette smoking
  3. Chronic hyperglycemia
  4. Elevated Angiotensin II
123
Q

what is LDL oxidation ?

A

interaction of LDL with a reactive oxygen species that damages the LDL (can occur because any number of free radicals )

124
Q

LDL oxidation can occur for the 4 reasons mentioned previously and under conditions of chronic elevated _____ and reduced _____.

A

LDL

HDL

125
Q

Under harsh conditions (4 conditions listed previously), the entothelial cells will express receptors for inflammatory cells or _________, this allows them to move into the interstitial space between the ______ and _______ called the Intama.

A

Monocytes

endothelial layer

smooth muscle layer

126
Q

At the same time the Monocytes move into the Intama through receptors, the Elevated ______ are small enough to pass through the endothelial cells and can get trapped, then oxidized and taken up by ______ and convert the Macrophage to a ______ ____.

A

LDL

Macrophages

Foam cell

127
Q

What is a foam cell?

A

a Macrophage laden with oxidized LDLs and in the intama (space between the endothelial cells and smooth muscle cells of the vascular tissue)

128
Q

The accumulation of foam cells will ________ the Endothelial cells and ______ the vasculature. This happens because the smooth muscle will try to patch over the foam cells as they accumulate and forma core.

A

Dystend

Acclue

129
Q

The core that has accumulated the foam cells and the smooth muscle cells tried to patch will eventually become necrotic, and eventually rupture and form a _________ that can completely or partially acclued the vesicle.

A

thrombosis

130
Q

Statins will _______ _______ activity to control cholesterol. Reducing endogenous cholesterol synthesis.

A

Inhibit HMG-CoA reductase

131
Q

Bile acid resins will ______ ______ ______ of bile salts. Inhibiting the normal reabsorbtion process of Bile salts into the liver.

A

increase fecal excretion

132
Q

______can facilitate reducing cholesterol by activating ________ which will increase _______of VLDL particles.

A

Niacin

Lipoprotein lipase

Catabolism

133
Q

________ can activate LPL by antagonizing the PPARalpha. This will help reduce the cholesterol levels in the blood.

A

Fibrates

134
Q

_______ reduces intestinal absorption of free cholesterol from the gut lumen.

A

Ezetimibe (class of drugs)