6. Part B lipo biochem

Question 1

What is responsible for esterifing free cholesterol to CE

~ for example, excess free cholesterol can be stored~

Answer 1

ACAT (Acyl-CoA Acyctrasferase)

Question 2

regulates absorption of dietary cholesterol in liver, thus makes good pharmK target
esterifies free cholesterol–> CE

Answer 2

ACAT-2 (found in intestine and liver)

Question 3

Where is ACAT-1 and what is it’s role

Answer 3

in macrophages, foam cells, adrenocortico, skin&raquo_space;> key for foam cell formation and cholesterol homeostais in extra-hepatic tissues

Question 4

Fate of VLDL remants

Answer 4

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

Question 5

Virtually all LDL particles in plasma come from

Answer 5

VLDL

Question 6

LDL is enriched in:

LDL major apo is:

Answer 6

cholesterol and CE

apoB 100

Question 7

rate of removal of VLDL remnants is a derterminant of:

Answer 7

LDL production

Question 8

How is LDL made from VLDL

Answer 8

removal of residual TG via hepatic lipase facilitated by ApoE

Question 9

What ligand binds to LDL-R

Answer 9

apo100

**liver removes 75% of all LDL from plasma

Question 10

What else has LDL-Rs besides liver

Answer 10

muslces and adipocytes: they can also take up LDL thus cholesterol via receptor-mediated endocytosis

Question 11

Half life of:
chylomicron
VLDL
LDL

Answer 11

5-20 mins
30 mins to 1 hour
2.5 days

Question 12

Where in cell is LDL-R made

Answer 12

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

Question 13

What is the cause of autosomal dominant hypercholesterolemia?

Answer 13

mutation of LDL receptor (over 900 kinds)

see elevated plasma LDL

Question 14

What effect does throxine and estrogen have on LDL-R

Answer 14

they enhance LDL-R gene expression; thus ahve LDL lowering effects

Question 15

How do cells regulate LDL-R expression?

Answer 15

via TFs: SREBPs and SREBP cleavage activating protein called Scap

Question 16

A serine protease that decreases steady state level expression of LDL-R on hepatocyte

Answer 16

PCSK9

PCSK9/LDLr complex is internalized and targeted for lysosomal degredation —> end up with increased LDL

Question 17

what is better a GOF or LOF PCSK9 mutation

Answer 17

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)

Question 18

is Lp(a) good or bad?

Answer 18

its bad; risk factor for CVD

Question 19

an LDL-like particle where apoB is covalently bound to apolipoportein(a)

Answer 19

Lp(a)

Question 20

We see a ____ releationship btwn size of apo(a) isorform and Lp(a) plasma conc

Answer 20

inverse

Question 21

is anti-oxidant, anti-thrombic, reduces vascular adhesion molecules on endothelium, stims endothelial repair, lowers inflammation

Answer 21

HDL

Question 22

carries out reverse cholesterol transport

Answer 22

HDL

picks up cholesterol from peripheral cells–> takes to liver for excreation via bile

Question 23

Most and second most abundant protein in HDL

Answer 23

apoA-I most abundant
apoA-II second most
***made in liver and inetestine and necessary for normal HDL production

Question 24

***made in liver and inetestine and necessary for normal HDL production

Answer 24

ApoA-I and apoA-II

Question 25

Mutation in apoA-I lead to:

Answer 25

HDL deficiency and accerleated atherosclerosis | --> mutation reduce capacity of ApoA-I to activate LCAT

Question 26

Membrane transporter expressed in liver, intestine, macros to promote efflux of cellular phospholipd adn cholesterol to lipid-free apoA-I

Answer 26

ATP binding casset transporter (ABCA1)

Question 27

helps release free cholesterol to apoA-I to make DISCOIDAL HDL

Answer 27

ABCA1

Question 28

Result of defective ABCA1

Answer 28

reduced choesterol efflux to apoA1 and aquisition of cholesterol by HDL is decreased; reduced HDL levels

Question 29

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

Answer 29

Tangier disease

Question 30

How is preB HDL or discoidal HDL formed?

Answer 30

1. ABCA-1 adds phospholips + FC to apoA-I= discoidal HDL -mostly happens in intestine OR 2. Chylomicrons or VLDL--> TGs hydrolzed + loss of apoA-I and phospholipids--> forms preB HDL

Question 31

What must preBHDL aquire before LCAT helps form it's CE core?

Answer 31

preBHDL gets free unesterified cholesterol from cell membranes of tissues

Question 32

What is the enZ that forms the CE core of HDL by esterifying free chosterol?

Answer 32

LCAT: from liver and circulates in blood

Question 33

How does HDL become spherical instead of discoidal

Answer 33

LCAT keeps esterifying cholesterol--> CE moves to core and gets more spherical

Question 34

What activates LCAT?

Answer 34

apoA-I

Question 35

role of ABCG1 in HDL

Answer 35

promotes cholesterol efflux to HDL | alters distribution of cholesterol on cell membane so that HDL can remove it

Question 36

What exchanges lipids betwen LDL and HDL

Answer 36

Cholesteryl ester transfer protein (CETP)

Question 37

What does CETP do?

Answer 37

transfers CE from HDL to VLDL/LDL/IDL in exchange for TGs

Question 38

what catalyzes transfer of phospholipids between lipoprotein classes

Answer 38

phospholipid transfer protein (PLTP)

Question 39

PLTP takes excess FC and phospholipds from surface of chylomicrons and VLDL following hydrolysis of TG to___

Answer 39

HDL

Question 40

What is needed for maximal activity of LCAT

Answer 40

PLTP | --> bc plays key role in generating preB-HDL the major acceptor of cellular cholesterold

Question 41

When is HDL a good substrate for hepatic lipase?

Answer 41

once CETP and PLTP mediate lipid exchange and HDL is rich in TGs

Question 42

What does HL do?

Answer 42

hydrolyzes TG and PL to make smaller HDL particles that recirculate and aquire more FC from tissues

Question 43

Androgens ____ HL activity, thus will overall _____ HDL-C values

Answer 43

increase HL activity | decrease HDL-C

Question 44

Estrogen ____ HL activity but doesn't have as much of an effects as androges do

Answer 44

decrease HL activity

Question 45

hydrolyzes HDL phospholipds and makes smaller HDL particles that are catabolized faster

Answer 45

endothelial lipase

Question 46

over expression of Endothelial lipase reduced ____ and ____ levels to almost zezo

Answer 46

apoA-I and HDL

Question 47

What may inhibit EL activity?

Answer 47

apoAII

Question 48

What is our HDL receptor

Answer 48

Scavenger receptor BI (SR-BI) | seen in liver, ovaries, testes and adrenals

Question 49

mutations in SR-BI in humans confirmed:

Answer 49

SR-BI is key in maintaining plasma cholesterol levels and plays protective role against atherosclerosis

Question 50

During HDL catabolism, what is transferred to cells via SR-BI in 'selective uptake?

Answer 50

CE core so ONLY LIPD uptake entire HDL is NOT INTERNALIZED --> lipid depleated particle will re-enter circulation to pick up more cholesterol

Question 51

Where are apoA I and apoA II from HDL taken up and degraded

Answer 51

removed synchronously via liver and kidney

Question 52

When AMP rises; kinase phosphorylates HMG-CoA reductase which will:

Answer 52

decrease activity and decrease cholesterol synthesis | -

Question 53

Glucagon and epinephrine cascade leads to:

Answer 53

phosphoryaltion of HMG-CoA reductase to decrease activity and decrease cholesterol synthesis

Question 54

Insulin cascase lead to DEphosphorylation cascade causing:

Answer 54

increased activity of HMG CoA reductase = increased cholesterol synthesis

Question 55

At low sterol levels; SREB-Scap is cleaved and moves to nucleus-->

Answer 55

increases HMGCoA reducatse and increaes LDL-R synthesis