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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
after triglyceride hydrolyzation, VLDL become what?
IDL (intermediate density lipoprotein)
26
what apolipoproteins are found on IDL?
same as VLDL: Apo B-100, Apo CII, Apo E
27
what is Apo CIII?
inhibitor of LPL
28
what determines how much LPL functions?
the balance between Apo CII (co-factor) and Apo CIII (inhibitor)
29
what happens to IDL?
some IDL go to the liver; some interact with hepatic lipase which hydrolyzes triglycerides to FFA and glycerol and make them become LDL
30
when triglycerides are broken down, where to they go?
to muscle and adipose tissue to get used for energy or go back to triglyceride form to get stored by cells in LIPIDD VESICLES
31
why do triglycerides get broken down to glycerol and fatty acids if they go back to triglyceride form when they are stored?
because glycerol is soluble in water and can cross the membrane and not triglycerides (they are hydrophobic)
32
LPL hydrolyzes triglycerides from what lipoproteins?
chylomicrons and VLDLs only
33
what do LDL contain?
mostly cholesterol ester, very little triglycerides (unlike chylomicrons and VLDL)
34
what is LPLD?
LPL deficiency, a rare recessive disorder caused by genetic mutations that causes chylomicrons and VLDLs to accumulate
35
what are the symptoms of LPLD?
pancreatitis, high triglyceride levels, atherosclerosis
36
what is the treatment for LPLD? how does it work?
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
where do LDLs go?
to peripheral tissue
38
what apolipoproteins are found on LDL?
ApoB-100and ApoE
39
where is un-esterized (free) cholesterol found in LDLs?
in the membrane around the core that contains esterified cholesterol
40
what are the main components of LDLR?
AopE/B binding domains, EGFP domain, six bladed propeller structure, TM domain, cytoplasmic domain
41
explain the LDLR intramolecular switch
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
what's the role of LDLR C terminus (cytoplasmic domain)?
recruits the complex to clathrin coated vesicles
43
once endocytosed, where do LDL go?
lysosomes
44
what happens to LDL in the lysosome?
- 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
what do NPC1/2 do?
carry cholesterol (chaperone) in lysosomes to the lysosomal membrane
46
what "type" of cholesterol transport does HDL do?
reverse cholesterol transport from tissues back to the liver
47
what is familial hypercholesterolemia?
deficiency in LDLR causing LDL to remain in the blood and become damaged -> attract macrophages -> cause atherosclerosis
48
what do macrophages become when they take up too much cholesterol?
foam cells
49
how do foam cells cause atherosclerosis?
foam cells recruit more macrophages and LDL which form a plaque which further oxidizes LDL
50
what are the causes of atherosclerosis?
- mostly high LDL concentration - also dysfunction of endothelial cells causing lesions
51
what is PCSK9?
a regulatory protease that attaches and internalizes LDLR into lysosomes to promote their destruction even when there is no LDL
52
what is PCSK9's effect on LCL-C plasma concentration?
it increases LDL-C plasma concentration
53
what is PCSK9i?
PCSK9 inhibitor: monoclonal antibody (prevents LDLR endocytosis and destruction by lysosomes)
54
what can PCSK9 be used for?
it can be used as an alternative to statins to treat high blood LDL-cholesterol / can be used WITH statins
55
clinically, what is the effect of PCSK9i?
reduces CVD events in individuals with CVD or at high risk of developing it
56
PCSK9 binds to what on LDLR?
EGFH domain
57
what is required for PSCK9i to work at lowering cholesterol / CVD / atherosclerosis?
you absolutely need a functional LDLR
58
what apolipoprotein is found on HDL?
ApoA-1
59
how are HDL formed?
ApoA-1 synthesized by liver + cholesterol extracted from macrophages and peripheral cells
60
what enzyme turn disk-like nascent HDL into round mature HDL? how does it do it?
LCAT: it esterifies the cholesterol at the surface
61
what is free cholesterol?
UNesterified cholesterol
62
what is CETP?
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
what protein is involved in generating nascent HDL? how does it work?
ABCA1: floppase that generates domains rich in cholesterol and phospholipids to which apoA-I can bind
64
what is the precise step that triggers the formation of nascent HDL?
Lipidation of apoA-I causes its release from the cell membrane to form nascent HDL
65
how does ApoA-1 form HDL disks?
it forms an amphipathic helix once it interacts with lipid and cholesterol rich domains and can detach from membrane
66
the cholesterol efflux that leads to nascent HDL formation prevents what?
macrophages to become foam cells, thus preventing atherosclerosis by removing cholesterol
67
what is dalcetrapid?
drug that increases HDLCs by inhibiting CETP mediated transfer of cholesterol ester and triglycerides
68
why did dalcetrapid not work?
it increased only pre-HDL, not mature ones, therefore inhibited the return of cholesterol to the liver
69
what is Tangier disease?
severe deficiency/absence of HDL, resulting in accumulation of cholesteryl esters and atherosclerosis
70
what causes the HDL deficiency in Tangier disease?
defect in ABCA1
71
what receptor do HDL bind to on the liver?
SR-B1 (direct pathway) or LDLR (indirect pathway)
72
what is SREBP?
ER protein to which HDL bind that serves as a TF for cholesterol-synthesis genes; found on liver
73
what is SCAP?
SREBP cleavage activating protein: ER protein that brings SREBP to the golgi; also binds cholesterol
74
what is INSIG?
ER protein that binds the sterol sensing domain of SCAP and cholesterol
75
what happens to the 3 regulatory proteins when cholesterol levels are high in the ER? what is the consequence?
INSIG binds hydroxysterols; SCAP binds cholesterol; INSIG keeps SREBP-SCAP complex in the ER; this INHIBITS cholesterol synthesis
76
what happens to the 3 regulatory proteins when cholesterol levels are low in the ER?
INSIG dissociates from SCAP; SCAP COPII binding domain is exposed; SCAP/SREBP are trafficked to the golgi via COP-II vesicles
77
what happens to SCAP/SREBP when they get to the golgi? what is the final outcome?
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
what are S1P and S2P?
site 1/2 proteases found in the golgi that cleave SREBP to activate it
79
what is special about S2P?
it cleaves IN the bilayer, in the hydrophobic domain
80
what happens to SCAP after SREBP goes to nucleus?
SCAP goes back to the ER
81
what happens to SREBP-2 localization under LDL exposure vs no LDL?
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
what regulates the level of HMG-CoA reductase?
the amount of cholesterol in the ER
83
what are neutral residues?
hydrophobic residues
84
how are LIPID DROPLETS generated?
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
briefly how do statins work?
inhibit HMG-CoA reductase which inhibits cholesterol formation
86
how does inhibiting HMG-CoA reductase lower cholesterol?
- inhibits mevalonic acid production by HMG-CoA reductase, which cholesterol is derived from - low cholesterol synthesis = activate SREBP processing -> increase LDL uptake
87
what are side effects of statins?
SAMS (muscle symptoms), type 2 diabetes, neurological effects, hepatotoxicity
88
where do the side effects from statins come from?
inhibits downstream steps between HMG-CoA reductase like protein prenylation, farnesyl, which affects inflammation and tissue remodeling
89
LDLR allow for what?
uptake of cholesterol, removing it from the circulation

ANAT458 (10 decks)

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