assembly of HDL Flashcards
what is an initial step involved in reverse cholesterol transport
The synthesis of preβ-HD
what are essential things for the synthesis of preβ-HD
ApoA-I and ABCA1
what is the major protein component of
HDL
ApoA-I
what are the functions of ApoA-I
– maintaining the structure of HDL
– interacting with lipid transporters (ABCA1)
– activating lecithin:cholesterol acyltransferase
(LCAT)
– antioxidant
what synthesizes and secretes ApoA-I
the liver and intestine
is ApoA-I exchangeable or not
it is
how many ApoA-I molecules can reside on chylomicrons and HDL
multiple
what is preβ-HDL, how does its density differ to mature HDL
- 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)
what is the percent mass of preβ-HDL
By percent mass, it is almost exclusively
protein than lipid
size of all the HDLs and preβ-HDL
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
what is cholesterol efflux
Cholesterol efflux is the transfer of
cholesterol (and phospholipid) from cells
to HDL
why is cholesterol efflux essential
Cholesterol efflux to apoA-I is essential for
generating preβ-HDL and ‘mature’ HDL
how is the efflux to apoA-I done
via ABCA1
what is another form of cholesterol efflux that occurs and via what
Cholesterol efflux to ‘mature’ HDL also
occurs, but it is not essential
– Efflux via ABCG1 and SR-BI
The conversion of nascent HDL to mature
HDL in the circulation requires
one key
enzyme and a “transfer protein”:
what is the one key enzyme and a transfer protein required for conversion of nascent HDL to mature HDL
– Lecithin:cholesterol acyl transferase (LCAT)
– Phospholipid transfer protein (PLTP)
what is a cofactor for LCAT activity
apoA-I
what provides phospholipids to HDL in the circulation
PLTP
what does PLTP do
PLTP transfers excess phospholipid from
apoB100-containing lipoproteins to HDL.
importance of PLTP
– 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.
ABCG1 functions
- ABCG1 functions similarly to ABCA1
- ABCG1 effluxes cholesterol (and
phospholipid) to ‘mature’ HDL
SR-BI structure
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
where is SR-BI expressed
in most tissues
function of SR-BI
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)
what HDLs carry TGs
HDL 1, 2, 3
how do TGs get into HDL 1-3
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)
is CETP good or bad
- 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
Torcetrapib (Pfizer)
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
Anacetrapib (Merck):
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
blood plasma before and after a meal
it is chylomicron rich post prandial (after a meal) and same with alcohol intake
where is LPL lipoprotein lipase found
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
what does LPL do
TG-DIGLYCERIDE-MONOGLYCERIDE
Releases FA each step and uses H2O in each step
what activates and inactivates LPL
activation by apoC-II and
inactivation by apoC-III
what does activation by apoC-II of LPL lead to
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
lipase activity on phospholipids
turns phospholipids to lysophospholipid
using H20 and releasing fatty acid
where is LPL expressed
heart, skeletal muscle, adipose
tissue, liver, spleen, lung, monocyte-
derived macrophages
where is HL expressed
liver, adrenal tissue, ovaries,
monocyte-derived macrophages
where is EL expressed
placenta, thyroid, liver, lung, kidney,
arterial/venal endothelial cells, monocyte-
derived macrophages
what are the substrate preferences of the different lipases due to
structural differences with the catalytic site
and putative lipid binding domains
what does EL prefer for substrate
phospholipid
what does LPL prefer for substrate
acylglyceride
what does HL prefer for substrate
either phsospholipid or acylglyceride
what lipase majorly acts on IDL
HL
what lipase majorly acts on VLDL
LPL
what lipase majorly acts on HDL1 to get to HDL 2
HL
what lipase majorly acts on HDL2 to get to HDL3
EL and HL
what lipase majorly acts on HDL3 to get to nascent HDL
EL
what is used to get from nascnent HDL to HDL3-HDL2-HDL1
LCAT
what is used on chylomicrons to get chylomicron remenants
LPL and small amount of HL
what is not used to get between the different HDL types
LPL
what enxymes in small or large amounts are used to get between the different LDL, IDL, AND VLDL
all
HL, EL, LPL
where do the lipases bind
on the cell surfaces
what are the cofactors for the lipases
Unlike LPL, which is activated by apoC-II,
HL and EL have no known cofactors
what inhibits HL
ApoC-I is thought to inhibit HL
what inhibits LPL and EL
Cleavage by proprotein convertases inhibit
both LPL and EL
what are common structural features of the lipases
there is a caatlytic triad with ser, asp, his and a “lid”
LPL defficiency in humans
very rare, elevated TG (>1,000
mg/dl), low HDL-C (<5th percentile),
hyperchylomicronemia, GWAS show no
link to atherosclerosis
HL defficiency in humans
extremely rare, TG- and PL- enriched
LDL and HDL, β-VLDL, associated with
premature atherosclerosis
EL defficiency in humans
extremely rare, elevated PL and HDL-
C (>95th percentile), association with
atherosclerosis unknown
EL defficiency in mice
modest ~50% elevations of TC and
PL, no atherosclerosis even on
atherogenic backgrounds.
HL defficiency in mice
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.
LPL defficiency in mice
severely elevated TG (>12,000
mg/dl) and death within 48h due to
suffocation. Heterozygotes viable
mice that dont express HL or EL or HL/EL dko
smallest in dko, second smallest in HL ko and largest in EL ko
number of pup delivered, surival, and sucess in WT vs HL -/-
more in HL -/-
what happned to HL/EL dko neonates
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
Spontaneous deaths over 3 mo.
in lipase-deficient mice
EL knockour- second smlallest
HL knockout- smallest
Deaths in HL/EL-dko highest due to infection, secondary to poor healing of umbilicus
