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ANAT458 > Cholesterol Transport and Metabolism (lect 10-11) > Flashcards

Cholesterol Transport and Metabolism (lect 10-11) Flashcards

1
Q

what is a lipoprotein?

A

circulating lipid carrier composed of a neutral lipid core, a monolayer of polar surface lipids and at least one apolipoprotein

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2
Q

what are apolipoproteins?

A

amphipathic proteins that insert in lipoproteins and serve as ligand for lipoprotein recognition and docking

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3
Q

what is the most dense type of lipoprotein?

A

HDL: high density lipoprotein

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4
Q

what is the least dense type of lipoprotein?

A

Chylomicrons

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5
Q

what is the biggest type of lipoprotein?

A

chylomicron

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6
Q

what happens to the dietary lipids we ingest?

A

they get absorbed in our small intestine and secreted in our bloodstream in form of chylomicrons

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7
Q

what happens to chylomicrons in the bloodstream?

A

their apolipoproteins activate LPL which hydrolyzes the triglycerides into FFA that are taken up by muscle and adipose tissue

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8
Q

what do chylomicrons become after interacting with LPL?

A

chylomicron remnants

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9
Q

where do chylomicrons remnants go? how do they interact?

A

to the liver, interacting via their apolipoproteins:
- ApoE interact with the LDLR in the liver
- ApoB-48 interacts with the LDLR related proteins

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10
Q

what happens to chylomicron remnants after they enter the liver?

A

the liver packages the lipids into VLDL that go in the circulation

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11
Q

where in the CELL are VLDL made?

A

in the ER membrane

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12
Q

what are the steps of the formation of pre-VLDL?

A
  1. translocation of ApoB to the inner ER membrane; ApoB interacts with MTP
  2. MTP transfers neutral lipids between the ER membrane leaflets to generate a neutral lipid core
  3. Pre-VLDL bulges out the INNER ER membrane
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13
Q

What is MTP?

A

microsomal transfer protein

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14
Q

Pre-VLDL bulges out from which leaflet of the ER membrane?

A

from the INNER leaflet

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15
Q

how are VLDLs transported from the ER to the golgi?

A

via VTVs (VLDL transport vesicle)

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16
Q

what proteins are involved in VTV budding? what vesicle is that?

A

Sar1b, Sec23/24, Sec12/31, ApoB-100.
COPII vesicles

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17
Q

what proteins are involved in VTV-Golgi fusion?

A

SNARE-complex, Sec22b (V-SNARE), other unimportant

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18
Q

what apolipoproteins are found on VLDL?

A

ApoB-100, ApoC, ApoE

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19
Q

what happens to VLDL in the circulation?

A

just like chylomicrons, their apolipoproteins activate LPL which hydrolyzes the triglycerides into FFA

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20
Q

what apolipoproteins are found on chylomicrons vs VLDL?

A

chylomicrons = Apo B-48, Apo C, Apo E, Apo A (I, II, IV)
VLDL = Apo B-100, Apo C, Apo E

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21
Q

what is the difference between Apo B-100 and Apo B-48?

A

Apo B-48 is 48% the lenght of Apo B-100

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22
Q

again where do chylomicrons originate from?

A

intestine

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23
Q

what kind of molecules are transported by chylomicrons vs VLDLs?

A

chylomicrons = dietary triglycerides and cholesterol from the intestine to the liver
VLDL = endogenous triglycerides from the liver to tissues

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24
Q

what is Apo C II?

A

a co-factor of LPL

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25
Q

after triglyceride hydrolyzation, VLDL become what?

A

IDL (intermediate density lipoprotein)

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26
Q

what apolipoproteins are found on IDL?

A

same as VLDL: Apo B-100, Apo CII, Apo E

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27
Q

what is Apo CIII?

A

inhibitor of LPL

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28
Q

what determines how much LPL functions?

A

the balance between Apo CII
(co-factor) and Apo CIII (inhibitor)

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29
Q

what happens to IDL?

A

some IDL go to the liver;
some interact with hepatic lipase which hydrolyzes triglycerides to FFA and glycerol and make them become LDL

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30
Q

when triglycerides are broken down, where to they go?

A

to muscle and adipose tissue to get used for energy or go back to triglyceride form to get stored by cells in LIPIDD VESICLES

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31
Q

why do triglycerides get broken down to glycerol and fatty acids if they go back to triglyceride form when they are stored?

A

because glycerol is soluble in water and can cross the membrane and not triglycerides (they are hydrophobic)

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32
Q

LPL hydrolyzes triglycerides from what lipoproteins?

A

chylomicrons and VLDLs only

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33
Q

what do LDL contain?

A

mostly cholesterol ester, very little triglycerides (unlike chylomicrons and VLDL)

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34
Q

what is LPLD?

A

LPL deficiency, a rare recessive disorder caused by genetic mutations that causes chylomicrons and VLDLs to accumulate

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35
Q

what are the symptoms of LPLD?

A

pancreatitis, high triglyceride levels, atherosclerosis

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36
Q

what is the treatment for LPLD? how does it work?

A

gene therapy: alipogene tiparvovec (Glybera)
- insert LPL gene in an AAV (adeno associated virus) and inject in muscle cells
-> gets replicated in the nucleus -> function LPL produced!

37
Q

where do LDLs go?

A

to peripheral tissue

38
Q

what apolipoproteins are found on LDL?

A

ApoB-100and ApoE

39
Q

where is un-esterized (free) cholesterol found in LDLs?

A

in the membrane around the core that contains esterified cholesterol

40
Q

what are the main components of LDLR?

A

AopE/B binding domains, EGFP domain, six bladed propeller structure, TM domain, cytoplasmic domain

41
Q

explain the LDLR intramolecular switch

A
  1. LDL binds LDLR on hepatocytes
  2. complex gets endocytosed
  3. pH and Ca2+ conc drops in endosome
  4. EGFP domain of LDLR folds, blocking the binding domain
  5. LDL ejected
42
Q

what’s the role of LDLR C terminus (cytoplasmic domain)?

A

recruits the complex to clathrin coated vesicles

43
Q

once endocytosed, where do LDL go?

A

lysosomes

44
Q

what happens to LDL in the lysosome?

A
  • Apo B is degraded in aa
  • ester cholesterol is hydrolyzed into FA and free cholesterol
  • NPC2 and NPC1 bind cholesterol and insert it in lysosomal membrane
45
Q

what do NPC1/2 do?

A

carry cholesterol (chaperone) in lysosomes to the lysosomal membrane

46
Q

what “type” of cholesterol transport does HDL do?

A

reverse cholesterol transport from tissues back to the liver

47
Q

what is familial hypercholesterolemia?

A

deficiency in LDLR causing LDL to remain in the blood and become damaged -> attract macrophages -> cause atherosclerosis

48
Q

what do macrophages become when they take up too much cholesterol?

A

foam cells

49
Q

how do foam cells cause atherosclerosis?

A

foam cells recruit more macrophages and LDL which form a plaque which further oxidizes LDL

50
Q

what are the causes of atherosclerosis?

A
  • mostly high LDL concentration
  • also dysfunction of endothelial cells causing lesions
51
Q

what is PCSK9?

A

a regulatory protease that attaches and internalizes LDLR into lysosomes to promote their destruction even when there is no LDL

52
Q

what is PCSK9’s effect on LCL-C plasma concentration?

A

it increases LDL-C plasma concentration

53
Q

what is PCSK9i?

A

PCSK9 inhibitor: monoclonal antibody (prevents LDLR endocytosis and destruction by lysosomes)

54
Q

what can PCSK9 be used for?

A

it can be used as an alternative to statins to treat high blood LDL-cholesterol / can be used WITH statins

55
Q

clinically, what is the effect of PCSK9i?

A

reduces CVD events in individuals with CVD or at high risk of developing it

56
Q

PCSK9 binds to what on LDLR?

A

EGFH domain

57
Q

what is required for PSCK9i to work at lowering cholesterol / CVD / atherosclerosis?

A

you absolutely need a functional LDLR

58
Q

what apolipoprotein is found on HDL?

A

ApoA-1

59
Q

how are HDL formed?

A

ApoA-1 synthesized by liver + cholesterol extracted from macrophages and peripheral cells

60
Q

what enzyme turn disk-like nascent HDL into round mature HDL? how does it do it?

A

LCAT: it esterifies the cholesterol at the surface

61
Q

what is free cholesterol?

A

UNesterified cholesterol

62
Q

what is CETP?

A

cholesteryl ester transfer protein: does the remodeling of HDL (from disk shape to round) by transferring triglycerides from VLDL to HDL and transferring cholesterol from HDL to VLDL

63
Q

what protein is involved in generating nascent HDL? how does it work?

A

ABCA1: floppase that generates domains rich in cholesterol and phospholipids to which apoA-I can bind

64
Q

what is the precise step that triggers the formation of nascent HDL?

A

Lipidation of apoA-I causes its release from the cell membrane to form nascent HDL

65
Q

how does ApoA-1 form HDL disks?

A

it forms an amphipathic helix once it interacts with lipid and cholesterol rich domains and can detach from membrane

66
Q

the cholesterol efflux that leads to nascent HDL formation prevents what?

A

macrophages to become foam cells, thus preventing atherosclerosis by removing cholesterol

67
Q

what is dalcetrapid?

A

drug that increases HDLCs by inhibiting CETP mediated transfer of cholesterol ester and triglycerides

68
Q

why did dalcetrapid not work?

A

it increased only pre-HDL, not mature ones, therefore inhibited the return of cholesterol to the liver

69
Q

what is Tangier disease?

A

severe deficiency/absence of HDL, resulting in accumulation of cholesteryl esters and atherosclerosis

70
Q

what causes the HDL deficiency in Tangier disease?

A

defect in ABCA1

71
Q

what receptor do HDL bind to on the liver?

A

SR-B1 (direct pathway) or LDLR (indirect pathway)

72
Q

what is SREBP?

A

ER protein to which HDL bind that serves as a TF for cholesterol-synthesis genes; found on liver

73
Q

what is SCAP?

A

SREBP cleavage activating protein: ER protein that brings SREBP to the golgi; also binds cholesterol

74
Q

what is INSIG?

A

ER protein that binds the sterol sensing domain of SCAP and cholesterol

75
Q

what happens to the 3 regulatory proteins when cholesterol levels are high in the ER? what is the consequence?

A

INSIG binds hydroxysterols; SCAP binds cholesterol; INSIG keeps SREBP-SCAP complex in the ER;
this INHIBITS cholesterol synthesis

76
Q

what happens to the 3 regulatory proteins when cholesterol levels are low in the ER?

A

INSIG dissociates from SCAP; SCAP COPII binding domain is exposed; SCAP/SREBP are trafficked to the golgi via COP-II vesicles

77
Q

what happens to SCAP/SREBP when they get to the golgi? what is the final outcome?

A

S1P and S2P cleaves SREBP; DNA-binding domain of SREBP is exposed; goes to nucleus and activates HMG-CoA reductase and LDLR transcription
-> increases cholesterol synthesis and uptake

78
Q

what are S1P and S2P?

A

site 1/2 proteases found in the golgi that cleave SREBP to activate it

79
Q

what is special about S2P?

A

it cleaves IN the bilayer, in the hydrophobic domain

80
Q

what happens to SCAP after SREBP goes to nucleus?

A

SCAP goes back to the ER

81
Q

what happens to SREBP-2 localization under LDL exposure vs no LDL?

A

SREBP-2 is found in the cell around the nucleus when there is LDL;
SREBP-2 is found at the nucleus when no LDL

82
Q

what regulates the level of HMG-CoA reductase?

A

the amount of cholesterol in the ER

83
Q

what are neutral residues?

A

hydrophobic residues

84
Q

how are LIPID DROPLETS generated?

A

in the liver, like VLDLs: neutral lipids (triglycerides and cholesteryl ester) are generated by acyl transferase and ACAT and accumulate in the ER membrane until the outer leaflet bulges out of the membrane

85
Q

briefly how do statins work?

A

inhibit HMG-CoA reductase which inhibits cholesterol formation

86
Q

how does inhibiting HMG-CoA reductase lower cholesterol?

A
  • inhibits mevalonic acid production by HMG-CoA reductase, which cholesterol is derived from
  • low cholesterol synthesis = activate SREBP processing -> increase LDL uptake
87
Q

what are side effects of statins?

A

SAMS (muscle symptoms), type 2 diabetes, neurological effects, hepatotoxicity

88
Q

where do the side effects from statins come from?

A

inhibits downstream steps between HMG-CoA reductase like protein prenylation, farnesyl, which affects inflammation and tissue remodeling

89
Q

LDLR allow for what?

A

uptake of cholesterol, removing it from the circulation

ANAT458 (10 decks)

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