assembly of HDL Flashcards

1
Q

what is an initial step involved in reverse cholesterol transport

A

The synthesis of preβ-HD

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2
Q

what are essential things for the synthesis of preβ-HD

A

ApoA-I and ABCA1

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3
Q

what is the major protein component of
HDL

A

ApoA-I

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4
Q

what are the functions of ApoA-I

A

– maintaining the structure of HDL
– interacting with lipid transporters (ABCA1)
– activating lecithin:cholesterol acyltransferase
(LCAT)
– antioxidant

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5
Q

what synthesizes and secretes ApoA-I

A

the liver and intestine

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6
Q

is ApoA-I exchangeable or not

A

it is

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7
Q

how many ApoA-I molecules can reside on chylomicrons and HDL

A

multiple

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8
Q

what is preβ-HDL, how does its density differ to mature HDL

A
  • As its name suggests, it is a type of HDL
    that has preβ-migrating properties (based
    on electrostatic charge)
  • It is a very small form of HDL with a
    density that is greater than ‘mature’ HDL
    (or HDL 1-HDL4)
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9
Q

what is the percent mass of preβ-HDL

A

By percent mass, it is almost exclusively
protein than lipid

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10
Q

size of all the HDLs and preβ-HDL

A

going from 1-4 they get smaller and the smallest is preβ-HDL

they decrease in the number of apo-a-i going from 1-4 to preβ-HDL

they have less to no fat and CE going from 1-4 to preβ-HDL

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11
Q

what is cholesterol efflux

A

Cholesterol efflux is the transfer of
cholesterol (and phospholipid) from cells
to HDL

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12
Q

why is cholesterol efflux essential

A

Cholesterol efflux to apoA-I is essential for
generating preβ-HDL and ‘mature’ HDL

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13
Q

how is the efflux to apoA-I done

A

via ABCA1

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14
Q

what is another form of cholesterol efflux that occurs and via what

A

Cholesterol efflux to ‘mature’ HDL also
occurs, but it is not essential
– Efflux via ABCG1 and SR-BI

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15
Q

The conversion of nascent HDL to mature
HDL in the circulation requires

A

one key
enzyme and a “transfer protein”:

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16
Q

what is the one key enzyme and a transfer protein required for conversion of nascent HDL to mature HDL

A

– Lecithin:cholesterol acyl transferase (LCAT)
– Phospholipid transfer protein (PLTP)

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17
Q

what is a cofactor for LCAT activity

A

apoA-I

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18
Q

what provides phospholipids to HDL in the circulation

A

PLTP

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19
Q

what does PLTP do

A

PLTP transfers excess phospholipid from
apoB100-containing lipoproteins to HDL.

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20
Q

importance of PLTP

A

– Provides phospholipid to expand the HDL surface
area.
– Provides lecithin (or phosphatidylcholine) for LCAT
activity.
– Contributes to the metabolism of apoB100-containing
lipoproteins into LDL.

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21
Q

ABCG1 functions

A
  • ABCG1 functions similarly to ABCA1
  • ABCG1 effluxes cholesterol (and
    phospholipid) to ‘mature’ HDL
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22
Q

SR-BI structure

A

SR-BI has both N- and C-terminal
transmembrane domains with the ends of
the protein exposed to the cytosol, while
the remainder is exposed to the circulation

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23
Q

where is SR-BI expressed

A

in most tissues

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24
Q

function of SR-BI

A

It has bidirectional function:
– In the liver it binds ‘mature’ HDL via its apoA-I
and brings cholesterol into the cells
(…selective uptake)
– In other tissues it binds ‘mature’ HDL via its
apoA-I and transfers cholesterol to HDL
(…cholesterol efflux)

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25
Q

what HDLs carry TGs

A

HDL 1, 2, 3

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26
Q

how do TGs get into HDL 1-3

A

In humans, the triglycerides come from
apoB-containing lipoproteins, in exchange
for cholesteryl esters from the HDL
* This transfer occurs in the bloodstream
through a transfer protein called
cholesteryl ester transfer protein (CETP)

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27
Q

is CETP good or bad

A
  • ApoB-containing lipoproteins are normally removed faster from the circulation vs. HDL, thus cholesteryl esters can be efficiently removed before they can lead to any detrimental effects
  • HDL containing excess triglyceride have a reduced capacity to accept cholesterol via efflux, and the HDL is rapidly metabolized leading to apoA-I catabolism
28
Q

Torcetrapib (Pfizer)

A

used in an attempt to inhibit CETP and raise HDL

– Increased HDL levels
– Increased apoA-I
– Lowered LDL b
– Raised blood pressure
* Increased mortality after 2 years

29
Q

Anacetrapib (Merck):

A

used in an attempt to incerase HDL by inhibiting CETP

– Increased HDL levels
– Increased apoA-I
– Lowered LDL
– Very modest increase of blood pressure

thorugh a trail they found that A small 9% reduction of CAD risk was observed
but it was attributed ONLY to the lowering of LDL
and not raising HDL

30
Q

blood plasma before and after a meal

A

it is chylomicron rich post prandial (after a meal) and same with alcohol intake

31
Q

where is LPL lipoprotein lipase found

A

Lipoprotein lipase (LPL) is anchored to the cell surfaces of several tissues that are
exposed to the circulation

The highest levels of expression of LPL
are within the heart and adipose

32
Q

what does LPL do

A

TG-DIGLYCERIDE-MONOGLYCERIDE

Releases FA each step and uses H2O in each step

33
Q

what activates and inactivates LPL

A

activation by apoC-II and
inactivation by apoC-III

34
Q

what does activation by apoC-II of LPL lead to

A

before apoC-II dissociates, activation of LPL leads to FA being delivered

TG depletion causes apoC-II to dissociate which leads to bound apoC-III to inhibiti LPL in the absence of ApoC-II remaning it was always there

35
Q

lipase activity on phospholipids

A

turns phospholipids to lysophospholipid

using H20 and releasing fatty acid

36
Q

where is LPL expressed

A

heart, skeletal muscle, adipose
tissue, liver, spleen, lung, monocyte-
derived macrophages

37
Q

where is HL expressed

A

liver, adrenal tissue, ovaries,
monocyte-derived macrophages

38
Q

where is EL expressed

A

placenta, thyroid, liver, lung, kidney,
arterial/venal endothelial cells, monocyte-
derived macrophages

39
Q

what are the substrate preferences of the different lipases due to

A

structural differences with the catalytic site
and putative lipid binding domains

40
Q

what does EL prefer for substrate

A

phospholipid

41
Q

what does LPL prefer for substrate

A

acylglyceride

42
Q

what does HL prefer for substrate

A

either phsospholipid or acylglyceride

43
Q

what lipase majorly acts on IDL

A

HL

44
Q

what lipase majorly acts on VLDL

A

LPL

45
Q

what lipase majorly acts on HDL1 to get to HDL 2

A

HL

46
Q

what lipase majorly acts on HDL2 to get to HDL3

A

EL and HL

47
Q

what lipase majorly acts on HDL3 to get to nascent HDL

A

EL

48
Q

what is used to get from nascnent HDL to HDL3-HDL2-HDL1

A

LCAT

49
Q

what is used on chylomicrons to get chylomicron remenants

A

LPL and small amount of HL

50
Q

what is not used to get between the different HDL types

A

LPL

51
Q

what enxymes in small or large amounts are used to get between the different LDL, IDL, AND VLDL

A

all
HL, EL, LPL

52
Q

where do the lipases bind

A

on the cell surfaces

53
Q

what are the cofactors for the lipases

A

Unlike LPL, which is activated by apoC-II,
HL and EL have no known cofactors

54
Q

what inhibits HL

A

ApoC-I is thought to inhibit HL

55
Q

what inhibits LPL and EL

A

Cleavage by proprotein convertases inhibit
both LPL and EL

56
Q

what are common structural features of the lipases

A

there is a caatlytic triad with ser, asp, his and a “lid”

57
Q

LPL defficiency in humans

A

very rare, elevated TG (>1,000
mg/dl), low HDL-C (<5th percentile),
hyperchylomicronemia, GWAS show no
link to atherosclerosis

58
Q

HL defficiency in humans

A

extremely rare, TG- and PL- enriched
LDL and HDL, β-VLDL, associated with
premature atherosclerosis

59
Q

EL defficiency in humans

A

extremely rare, elevated PL and HDL-
C (>95th percentile), association with
atherosclerosis unknown

60
Q

EL defficiency in mice

A

modest ~50% elevations of TC and
PL, no atherosclerosis even on
atherogenic backgrounds.

61
Q

HL defficiency in mice

A

modest ~30% elevations of TC and
PL, no atherosclerosis without additional
genetic modification.
* EL: modest ~50% elevations of TC and
PL, no atherosclerosis even on
atherogenic backgrounds.

62
Q

LPL defficiency in mice

A

severely elevated TG (>12,000
mg/dl) and death within 48h due to
suffocation. Heterozygotes viable

63
Q

mice that dont express HL or EL or HL/EL dko

A

smallest in dko, second smallest in HL ko and largest in EL ko

64
Q

number of pup delivered, surival, and sucess in WT vs HL -/-

A

more in HL -/-

65
Q

what happned to HL/EL dko neonates

A

A small number of HL/EL-dko neonates
lacked abdominal organs. (Not observed
with HL-ko and EL-ko litters).

indicating that HL and EL may play a combined role in fetal development

66
Q

Spontaneous deaths over 3 mo.
in lipase-deficient mice

A

EL knockour- second smlallest

HL knockout- smallest

Deaths in HL/EL-dko highest due to infection, secondary to poor healing of umbilicus

67
Q
A