6. Part B lipo biochem Flashcards
What is responsible for esterifing free cholesterol to CE
~ for example, excess free cholesterol can be stored~
ACAT (Acyl-CoA Acyctrasferase)
regulates absorption of dietary cholesterol in liver, thus makes good pharmK target
esterifies free cholesterol–> CE
ACAT-2 (found in intestine and liver)
Where is ACAT-1 and what is it’s role
in macrophages, foam cells, adrenocortico, skin»_space;> key for foam cell formation and cholesterol homeostais in extra-hepatic tissues
Fate of VLDL remants
once LPL shrinks VLDL–> goes back to circulation and withing 30 mins will either
-get cleared by liver via liver LDL receptors and LRP
OR
-LPL and hpatic lipase convert–> to LDL by removing TGs
Virtually all LDL particles in plasma come from
VLDL
LDL is enriched in:
LDL major apo is:
cholesterol and CE
apoB 100
rate of removal of VLDL remnants is a derterminant of:
LDL production
How is LDL made from VLDL
removal of residual TG via hepatic lipase facilitated by ApoE
What ligand binds to LDL-R
apo100
**liver removes 75% of all LDL from plasma
What else has LDL-Rs besides liver
muslces and adipocytes: they can also take up LDL thus cholesterol via receptor-mediated endocytosis
Half life of:
chylomicron
VLDL
LDL
5-20 mins
30 mins to 1 hour
2.5 days
Where in cell is LDL-R made
made on the RER and then moves to plasma membrane via golgi apparatus
otherwise it is segregated into a vesicle post endocytosis and recycled back to surface
What is the cause of autosomal dominant hypercholesterolemia?
mutation of LDL receptor (over 900 kinds)
see elevated plasma LDL
What effect does throxine and estrogen have on LDL-R
they enhance LDL-R gene expression; thus ahve LDL lowering effects
How do cells regulate LDL-R expression?
via TFs: SREBPs and SREBP cleavage activating protein called Scap
A serine protease that decreases steady state level expression of LDL-R on hepatocyte
PCSK9
PCSK9/LDLr complex is internalized and targeted for lysosomal degredation —> end up with increased LDL
what is better a GOF or LOF PCSK9 mutation
LOF mutation: then we get higher levels of LDL-R thus lower LDL-C levles = protects from CHD
(GOF makes more PCSK9 binding and internalizing and ddestroying LDL-R = bad)
is Lp(a) good or bad?
its bad; risk factor for CVD
an LDL-like particle where apoB is covalently bound to apolipoportein(a)
Lp(a)
We see a ____ releationship btwn size of apo(a) isorform and Lp(a) plasma conc
inverse
is anti-oxidant, anti-thrombic, reduces vascular adhesion molecules on endothelium, stims endothelial repair, lowers inflammation
HDL
carries out reverse cholesterol transport
HDL
picks up cholesterol from peripheral cells–> takes to liver for excreation via bile
Most and second most abundant protein in HDL
apoA-I most abundant
apoA-II second most
***made in liver and inetestine and necessary for normal HDL production
***made in liver and inetestine and necessary for normal HDL production
ApoA-I and apoA-II
Mutation in apoA-I lead to:
HDL deficiency and accerleated atherosclerosis
–> mutation reduce capacity of ApoA-I to activate LCAT
Membrane transporter expressed in liver, intestine, macros to promote efflux of cellular phospholipd adn cholesterol to lipid-free apoA-I
ATP binding casset transporter (ABCA1)
helps release free cholesterol to apoA-I to make DISCOIDAL HDL
ABCA1
Result of defective ABCA1
reduced choesterol efflux to apoA1 and aquisition of cholesterol by HDL is decreased; reduced HDL levels
Loss of function of ABCA1; thus low levels of HDL and CE accumulation in liver, intestines, spleen, tonsils
can’t form spherical or discoidal HDL with LOW plasma cholesterol
Tangier disease
How is preB HDL or discoidal HDL formed?
- ABCA-1 adds phospholips + FC to apoA-I= discoidal HDL
-mostly happens in intestine
OR - Chylomicrons or VLDL–> TGs hydrolzed + loss of apoA-I and phospholipids–> forms preB HDL
What must preBHDL aquire before LCAT helps form it’s CE core?
preBHDL gets free unesterified cholesterol from cell membranes of tissues
What is the enZ that forms the CE core of HDL by esterifying free chosterol?
LCAT: from liver and circulates in blood
How does HDL become spherical instead of discoidal
LCAT keeps esterifying cholesterol–> CE moves to core and gets more spherical
What activates LCAT?
apoA-I
role of ABCG1 in HDL
promotes cholesterol efflux to HDL
alters distribution of cholesterol on cell membane so that HDL can remove it
What exchanges lipids betwen LDL and HDL
Cholesteryl ester transfer protein (CETP)
What does CETP do?
transfers CE from HDL to VLDL/LDL/IDL in exchange for TGs
what catalyzes transfer of phospholipids between lipoprotein classes
phospholipid transfer protein (PLTP)
PLTP takes excess FC and phospholipds from surface of chylomicrons and VLDL following hydrolysis of TG to___
HDL
What is needed for maximal activity of LCAT
PLTP
–> bc plays key role in generating preB-HDL the major acceptor of cellular cholesterold
When is HDL a good substrate for hepatic lipase?
once CETP and PLTP mediate lipid exchange and HDL is rich in TGs
What does HL do?
hydrolyzes TG and PL to make smaller HDL particles that recirculate and aquire more FC from tissues
Androgens ____ HL activity, thus will overall _____ HDL-C values
increase HL activity
decrease HDL-C
Estrogen ____ HL activity but doesn’t have as much of an effects as androges do
decrease HL activity
hydrolyzes HDL phospholipds and makes smaller HDL particles that are catabolized faster
endothelial lipase
over expression of Endothelial lipase reduced ____ and ____ levels to almost zezo
apoA-I and HDL
What may inhibit EL activity?
apoAII
What is our HDL receptor
Scavenger receptor BI (SR-BI)
seen in liver, ovaries, testes and adrenals
mutations in SR-BI in humans confirmed:
SR-BI is key in maintaining plasma cholesterol levels and plays protective role against atherosclerosis
During HDL catabolism, what is transferred to cells via SR-BI in ‘selective uptake?
CE core so ONLY LIPD uptake
entire HDL is NOT INTERNALIZED
–> lipid depleated particle will re-enter circulation to pick up more cholesterol
Where are apoA I and apoA II from HDL taken up and degraded
removed synchronously via liver and kidney
When AMP rises; kinase phosphorylates HMG-CoA reductase which will:
decrease activity and decrease cholesterol synthesis
-
Glucagon and epinephrine cascade leads to:
phosphoryaltion of HMG-CoA reductase to decrease activity and decrease cholesterol synthesis
Insulin cascase lead to DEphosphorylation cascade causing:
increased activity of HMG CoA reductase = increased cholesterol synthesis
At low sterol levels; SREB-Scap is cleaved and moves to nucleus–>
increases HMGCoA reducatse and increaes LDL-R synthesis
