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CV > 092614 lipids > Flashcards

092614 lipids Flashcards

1
Q

fates of cholesterol

A

some examples:
sex hormones
mineralcorticoids
glucocorticoids

vitamin D

primary bile acids

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2
Q

how is cholesterol cytotoxic?

A

excess cholesterol can lead to:

formation of cholesterol crystals

triggering of apoptosis

formation of toxic oxysterols

disruption of membrane domains that are crucial for fxn of enzymes and signaling molecules

contribute to machanisms that promote atherosclerosis

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3
Q

four steps of cholesterol synthesis

A

three acetates condense to make mevalonate

mevalonate converted to phosphorylated 5-C isoprene

six isoprenes polymerize to make 30-C linear squalene

squalene cyclizes to make four rings which are modified to make cholesterol

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4
Q

how is mevalonate made from acetyl-coA

A

2 acetyl coAs form acetyoacetyl-coA

then acetyl-coA and acetoacetyl-coA combine, in a step catalyzed by HMG-coA synthase, to form beta hydroxyl beta methylglutaryl-coA (HMG-coA)

HMG-coA and 2 NADPH, in a step catalyzed by HMG-coA reductase, form mevalonate

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5
Q

what is the rate limiting step in cholesterol synthesis

A

HMG-coA reductase

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6
Q

where is most cholesterol made

A

liver. then it is exported as bile acids, biliary cholesterol, or cholesteryl esters.

cholesteryl esters are the storage form of cholesterol

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7
Q

how are cholesteryl esters different from cholesterol

A

they are more non-polar than cholesterol b/c they have a fatty acid esterified to the oxygen

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8
Q

what happens to cholesteryl esters?

A

they are transported in lipoproteins to other tissues or stored in the liver

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9
Q

apolipoproteins

A

proteins on the surface of a lipoprotein particle, which is used to carry lipids through plasma

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10
Q

what does the interior of lipoprotein particles contain

A

cholesterol, triglycerides, cholesteryl esters

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11
Q

what does the surface of lipoprotein particles contain

A

apolipoproteins and phospholipid monolayer

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12
Q

which lipoproteins are atherogenic (found in plaques)

A 
VLDL
VLDL remnants
IDL
LDL
Lp (A)
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13
Q

what is a chylomicron made of primarily?

A

triglycerides

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14
Q

which lipoproteins have the highest content of triacylglycerls

A

chylomicrons

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15
Q

which kind of lipoproteins have the highest content of proteins and phospholipids

A

HDL

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16
Q

what are the core lipids of HDL?

A

cholesteryl ester

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17
Q

are apolipoproteins exchangeable or non-exchangeable

A

can be exchangeable and non-exchangeable

in the case of LDL-they are non-exchangeable

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18
Q

what can apolipoproteins do?

A

they can change conformation to adjust to changing lipid contents and metabolic states of the lipoproteins

they can activate or inhibit plasma enzymes

they serve as ligands for cell surface receptors

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19
Q

NPC1L1 does what

A

mediates intestinal cholesterol absorption

called Niemann Pick C1 Like 1 protein

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20
Q

ABCG5/G8 does what

A

export plant sterols back into the intestinal lumen

they are ATP-binding cassette (ABC) half transporters

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21
Q

exogenous pathway

A

dietary fats are packaged into chylomicrons

in the blodstream, lipoprotein lipase releases free fatty acids from the chylomicrons to give to the adipose tissue and muscle.

remnants of chylomicrons are taken up by liver. liver can use these remnants to make bile acids and cholesterol to release back to the intestine

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22
Q

sitosterolemia

A

autosomal recessive disorder with mutations in either of the genes that encode ABCG5 and ABCG8

result is that they absorb unusually large amounts of plant sterols, and because they fail to excrete these dietary sterols into the bile, they accumulate plant sterols in the blood and tissues

accumulation of plant sterols is associated with tendon and subcutnaoues xanthomas and increased risk of premature coronary heart disease

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23
Q

chylomicrons’ main apolipoprotein is

A

B-48

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24
Q

how long do chylomicrons remain in the blood after a fat-containing meal?

A

3-6 hours

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25
Q

role of ApoC-II in a chylomicron

A

activates lipoprotein lipase to allow free fatty acid release for fuel in adipose tissue, heart, skeletal musc

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26
Q

lipoprotein lipase

A

found on capillary endothelium in heart, skel musc, adipose tissue, mammary gland, etc

required for hydrolysis of fatty acids derived from triglycerides of chylomicrons and VLDL so that the fatty acids can be delivered to tissues

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27
Q

what do you get when lipoprotein lipase works on a chylomicron or VLDL?

A

shrunken triglyceride-rich particle (chylomicron remnants, IDL, and LDL). cholesterol, phospholipids, and apolipoproteins are transferred to HDL

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28
Q

when is LDL transcriptionally activated?

A

when glucose levels in plasma are elevated and the release of insulin is stimulated

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29
Q

during prolonged fasting, what would LPL activity be?

A

LPL activity of adipose tissue falls to prevent storage of fatty acids

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30
Q

when chylomicrons are depleted of their dietary triglyceride through LPL, what happens to their remnants?

A

remnants go to liver to release dietary cholesterol.
endocytosed at the liver through a process that requires apoE as a ligand for hepatic receptors like LDL receptor or the LDL receptor-related protein (LRP)

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31
Q

LRP’s significance

A

backup receptor for the uptake of apoE enriched remnants of chylomicrons and VLDL

32
Q

VLDL does what

A

transport endogenous lipids that the liver makes

VLDL is made by the liver when triglyceride production is stimulated by an increased flux of free fatty acids or by increased de novo synthesis of fatty acids by the liver

cholesteryl esters and triglycerides from excess fatty acids and cholesterol are packed into the core of VLDL and exported to peripheral tissues

33
Q

apolipoproteins of chylomicrons are acquired from where

A

some are made by intestinal epithelial cells and others are acquired from HDL after chylomicrons have been secreted into the lymph and enter plasma

34
Q

microsomal tryglyceride transfer protein does what

A

it transfers triglyceride to the VLDL core (after being made in the ER, triglyceride is transferred by MTP to newly made apoB-100 to make VLDL

also transfers triglyceride to chylomicrons in intestine

35
Q

pts with dysfunctional MTP have what happen

A

they fail to make any of the apoB-containing lipoproteins (chylomicrons, VLDL, LDL)

causes abetalipoproteinemia (fat in stool, vitamin deficiency, developmental delays)

36
Q

cholesterol ester

A

storage form of cholesterol

37
Q

endogenous cholesterol in excess of need for membrane synthesis is metabolized to cholesterol ester by what

A

ACAT (acyl-CoA cholesterol acyltransferase)

an important regulator of cellular cholesterol pool that serves as substrate for bile acid and steroid hormone production

38
Q

ACAT-2 is found where

A

intestine and liver, where cellular free cholesterol is esterified before triglyceride-rich lipoproteins (chylomicrons and VLDL) are assembled

39
Q

ACAT-1 is found where

A

macrophages including foam cells

40
Q

role of apoC-II in VLDL

A

same as for chylomicron-activates lipoprotein lipase

41
Q

VLDL have what two fates (their half life is less than 30 minutes)

A

40-60% are celared from plasma by the liver via LDL receptors and LRP which recognize ligands-apoB100 and apoE-on the remnants

LPL and hepatic lipase convert the remainder of the remnants/IDL to LDL by removing additional triglyceride

42
Q

just about all LDL particles in the plasma are derived from

A

VLDL

43
Q

LDL is enriched in

A

cholesterol or cholesteryl esters

44
Q

what determines LDL production

A

rate of removal of VLDL remnants

45
Q

LDL does what

A

deposits cholesterol in peripheral tissues

46
Q

what enables binding of LDL to LDL receptor

A

apoB-100

47
Q

what is the most effective way to modulate plasma LDL levels?

A

manipulation of hepatic LDL receptor gene expression (because the liver expresses a large complement of LDL receptors and is responsible for removing 75% of all LDL in the plasma)

48
Q

what other tissues have LDL receptors other than the liver?

A

muscle and adipose tissue

49
Q

half life of LDL

A

2.5 days

50
Q

most common cause of autosomal dominant hypercholesterolemia

A

mutation of LDL receptor gene

51
Q

regulation of LDL receptor expression is mediated by

A

transcription factors called sterol regulatory element binding proteins (SREBPs) and SREBP cleavage activating protein (Scap)

52
Q

proprotein convertase subtilisin/kexin type 9 (PCSK9)

A

serine protease that decreases the steady state level of expression of LDL receptor on the hepatocyte cell membrane (binds to the EGF-A domain of LDLR and causes internalization and targeting to lysosome)

high interest in this as a cholesterol lowering target!

53
Q

lipoprotein (a) or Lp(a) is

A

an LDL-like particle where apoB-100 is covalently bound to apolipoprotein(a)

half life in ciruclation is 3-4 days

a risk factor for CV disease

54
Q

what will LDL do eventually in peripheral tissues if HDL can’t kick in?

A

will eventually deposit cholesterol in peripheral tissues

HDL is good cholesterol in that it will do the opposite-it will take cholesterol from peripheral tissues and take it back to liver for excretion via bile

55
Q

how is HDL athero-protective

A 
anti oxidant
anti thrombotic
reduces vascular adhesion molecules on endothelium
stimulates endothelial repair
promotes endothelial fxn
lowers inflam
stabilizes atherosclerotic plaques
56
Q

most abundant proteins in HDL

A

HDL in general has a lot of protein!

apoA-I is most abundant
ApoA-II is second most abundant

(HDL also has C apolipoproteins and lecithin-cholesterol acyl transferase)

57
Q

ApoA-I mutations can

A

cause HDL deficiency

reduce capacity of apoA-I to activate LCAT

58
Q

ATP binding cassette transporter (ABCA1) does what

A

helps release free cholesterol to apoA-I to make discoidal HDL (promotes efflux of cellular phospholipid and cholesterol to lipid-free apoA-I)

59
Q

where is ATP binding cassette transporter (ABCA1) expressed

A

it’s a membrane transporter expressed in liver, intestine, macrophages, brain, other tissues

60
Q

loss of fxn mutations of ABCA1 result in what disease

A

Tangier disease-extremely low levels of HDL

61
Q

majority of prebeta-HDL (discoidal HDL) formation occurs where

A

liver and intestine (also the sites of apoA-I synthesis and ABCA1 expression)

62
Q

where is lecithin-cholesterol acyl transferase (LCAT) found

A

secreted by liver, circulates in blood and at times associated with HDL

63
Q

lecithin-cholesterol acyl transferase (LCAT) ‘s fxn is

A

to help form the cholesterol ester core of HDL-after free cholesterol is acquired by the prebeta HDL, the free cholesterol is esterified by LCAT

64
Q

how does discoidal HDL become spherical?

A

through esterification of cholesterols–because esterified cholesterol is more hydrophobic and moves into the core to plump up the HDL

65
Q

apoA-I on HDL activates

A

LCAT

66
Q

ABCG1 does what

A

transfers cholesterol to spherical HDL

expressed in spleen, thymus, lung and brain, liver and macrophages

contributes to HDL remodeling

alters distribution of cholesterol on cells’ membranes and allows its removal by HDL

67
Q

cholesteryl ester transfer protein (CETP)

A

exchanges lipid btwn LDL and HDL-promotes transfer of cholesterol ester from HDL to VLDL, IDL and LDL in exchange for triglyceride

68
Q

scavenger receptor BI (SR-BI)

A

HDL receptor-a good receptor

expressed in liver, ovaries, testes, adrenal glands

69
Q

endothelial lipase

A

hydrolyzes HDL phospholipids, generating smaller HDL particles that are catabolized faster

modifies HDL to such an extent that it binds less to SR-BI

70
Q

selective uptake in the case of HDL binding to SR-BI

A

only lipid is transferred to cells (entire HDL particle is not internalized)

71
Q

enterohepatic circulation of cholesterol

A

in liver, cholesterol is secreted into bile either directly or after conversion to bile acids (cholesterol is converted to bile acids by cholesterol 7alpha hydroxylase)

however, only 5% of the bile salts are actually lost in feces–the rest gets reabsorbed by the intestines (this reabsorbed portion goes back to the liver by ENTEROHEPATIC CIRCULATION-so the bile salts are recycled)

72
Q

regulation of cholesterol synthesis and transport

A

covalent modification of HMG-coA reductase
transcriptional regulation of HMG-coA gene
activation of ACAT
transcriptional regulation of LDL receptor

73
Q

AMP dependent protein kinase regulates cholesterol metabolism how

A

when AMP rises, the kinase phosphorylates HMG-coA reductase, leading to decreased activity of HMG-coA reductase and decreased cholesterol synthesis

74
Q

SREBPs (sterol regulatory element binding proteins)

A

longer-term regulation of HMG-coA reductase through transcriptional control

this protein activates transcription of HMG-CoA reductase and LDL receptor

when cellular sterol levels are high, SREBP is not active

75
Q

do oxidized LDL bind to the same receptors as non-oxidized?

A

no, oxidized is taken up by scavenger receptors not LDL receptors

CV (34 decks)

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