Lightbody Lecture 15 and 16

Question 1

lipoprotein particles

Answer 1

Plipid, prot (apoprot), cholesterol (free and esterified), and TAG; transport lipids to periph tissues and return excess to liver; constant synth, transition, degrad, and removal from plasma; role in myo infarc, stroke, periph vasc disease, other inflam; synth in liver and intestine; heterogen in size and density; must go back to liver to be metab

Question 2

chylomicrons

Answer 2

90% TAG, 5% cholesterol, 2% prot (largest w/lowest density)

Question 3

VLDL

Answer 3

60% TAG, 20% chol, 5% prot; smaller and more dense than chylo

Question 4

LDL

Answer 4

4% TAG, 50% chol, 25% prot; smaller and more dense than chylo or VLDL; Plipid single layer memb interspersed w/free chol (unesterified); apoprots are on surface (some integ, some periph); one apoB100 per LDL, encircles like belt; inner core is chol ester and TG

Question 5

HDL

Answer 5

8% TAG, 30% chol, 33% prot; smallest and most dense

Question 6

apolipoproteins/apoproteins

Answer 6

on lipoprot particle surface; interact w/receps on cells, det fate of LPP; activate/inhib enz’s; each has unique set of apoprots; transferred from one LPP to another; diff isoforms (some assoc w/disease (AD-apoE)

Question 7

Apo A-I

Answer 7

most abund prot on HDL; maturation of HDL and efflux of chol from cells to HDL; bds to scavenger receps on liver cells, activates LCAT (esterifies chol to FAs)

Question 8

Apo B 100

Answer 8

req for form of VLDL; 1o prot of LDL, acts as ligand for LDL recep (LDLR) to allow chol deliv; v large (4400 AAs)

Question 9

Apo B 48

Answer 9

truncated form of apo B 100, synth’d in intestine and req’d for chylomicron formation; only on chylos

Question 10

Apo CII

Answer 10

on chylos, VLDL, HDL; activates lipoprotein lipase (LPL), exchanged b/w diff lipoprot classes

Question 11

Apo CIII

Answer 11

synth’d in liver and int, on chylos, VLDL, LDL, HDL; inv in inflam; high concs assoc w/cardiovasc disease

Question 12

Apo E

Answer 12

synth in liver on HDL, trans to chylos and VLDL, where acts as ligand for rem chylo remnants and IDL from circul thru LDL recep or LRP recep (E2-4); may clear amyloid fr brain

Question 13

Apo E4

Answer 13

genetic risk factor for late-onset AD; homozygote at 68y; hetero at 75; no alleles 84; E3 most common, but E4 have 20x risk of devel AD; E2 decreases risk

Question 14

chylomicrons

Answer 14

carry dietary TAG to other tissue to be used for E or stored; syn in enterocytes, sec into blood to LPL; resulting remnant endocytosed into liver, dig into individ cmpnts

Question 15

lipoprotein lipase (LPL)

Answer 15

on capil walls of endothel cells; hydrol TAG to FFAs (80% - other 20% goes to liver); activated by ApoCII

Question 16

intermed density lipoprot

Answer 16

formed in VLDL breakdown; 50% returns to liver, 50% becomes LDL (loses ApoE)

Question 17

lipoprot lipase deficiency

Answer 17

evident in infancy; pancreatitis, nausea, musc pain, fatty deposits (xanthomas); elevated chol, high triglycerides after 12h fast, normal apo CII; restrict dietary fat (<10g/d); inc carbs and prots; inc fat-sol vits; mortality b/c pancreatitis

Question 18

ApoE and Apo B 100 bdg

Answer 18

extended form on VLDL surface, can’t bind w/recep; VLDL dec in size as TAG hydrol by LPL, /\ing conform of ApoE and B100 and allows them to bd to LDL recep as VLDL transformed to IDL

Question 19

LDL fxn

Answer 19

derived from VLDL via IDL; has 4% TAG, 50% chol; main fxn is provide chol to periph tissue, return maj of excess to liver; 70% chol returned via LDL, rest via HDL; high assoc w/atherosclerosis, myo infarct, stroke, periph vasc disease (bad chol)

Question 20

small, dense LDL

Answer 20

300x more likely to cause myo infarct or stroke; predictor of cardiovasc events and CAD

Question 21

HDL

Answer 21

heterogeneous gp; synth in liver, some int; reservoir for CII and E; Apo A (combines w/scavenger recep on PM of liver instead of LDLR) is most abund prot on HDL surface; picks up free chol, esterifies it, transfers to LDL (70%) or VLDL or returns direc to liver (30% via HDL); at same t, VLDL and LDL transfer TAG to HDL; raised by exercise, low wt, no smoke, no trans fat, alcohol, omega FAs, niacin

Question 22

ABCA1-ATP bdg cassette transporter

Answer 22

bds to apo-AI–>transport of free chol from cell to HDL, where esterified by LCAT

Question 23

LCAT (lecithin-chol acyl transferase)

Answer 23

esterifies free chol to FAs; derived from PTC in HDL memb; activ by ApoA; not endocytosed into liver whole like LDL; puts chol in, then goes around again

Question 24

CETP

Answer 24

glycoprot, transfers chol esters from HDL to LDL and VLDL and TAGs from LDL and VLDL to HDL; struc is long tunnel assoc w/HDL; genetic defect in this causes low heart disease; block this–>block chol transfer

Question 25

CETP inhibitors

Answer 25

Torcetrapib; raised HDL a lot, lowered LDL a lot, lowered TG a little; 60% inc in mortality; now Anacetrapib, w/o these effects

Question 26

ApoCIII

Answer 26

small proinflam prot, on surface of chylos, VLDL, LDL, HDL; most abund apolipoprot in humans; high levels --> atherosclerosis and <3 disease; exact fxn unknown

Question 27

HDL

Answer 27

high levels-->low inc of atherosclerosis; women have higher levels and less low levels and high inc of <3 dis

Question 28

lipoprot receptors

Answer 28

memb receps; med internalization of lipoprot particle, allow cells to acquire chol and other lipids

Question 29

LDLRs

Answer 29

7TM gene family; on PM of many cells (esp liver); bds to ApoB100 (on VLDL and LDL) and apo E (on chylos, VLDL, IDL); removes 70% of chol from circul; 839 AAs, 18 exons; 6 Cys that're disulfide bonded; epidermal GF domain; oligosaccharide domain; transmemb; cyto domain

Question 30

scavenger receptors (SR)

Answer 30

bd to modified LDL (mLDL); also bd other anionic ligands; not subject to fdbk regulation like LDLR; on macs, dendritic cells, endothel cells

Question 31

LDLR epidermal GF homology domain

Answer 31

30%; 3 EGF repeats; 2 and 3 are sep by propeller region (sep LDL from receptor)

Question 32

cyto domain of LDLR

Answer 32

50 AAs; cont signal seq for internalization of receptor

Question 33

LDLR path and chol reg in liver

Answer 33

LDLRs are neg chg'd clustered in pits on memb; after bdg of LDL, whole complex endocytosed; LDLR sep fr LDL, recycled back to memb surface; LDL degraded by lysosomes, releasing free chol

Question 34

excess chol in liver reduced by

Answer 34

HMG CoA reductase syn., LDLR syn., HMG CoA reductase degrad (ubiquination), esterification (by ACAT-aCoA chol acyltransferase) and storage

Question 35

familial hypercholesterolemia

Answer 35

autosomal dominant; mutations in LDLR gene-->high chol levels (600-800mg/dl), premature absence/dysfxn of LDLR (1/2 in heteros); homos have xanthomas

Question 36

SR-A

Answer 36

on macs, endothel, sm m; recep for mLDL but not LDL; imp role in foam cell generation; no fdbk ctrl, so macs cont to accum chol (foam cells)

Question 37

SR-B

Answer 37

glycoprot w/509AA; large extracell loop w/2 TM domains; 8 Cys; on macs, adipocytes, liver; bd to LDL, mLDL, HDL; ApoA on HDL is ligand to this, plays role in transfer of chol fr HDL to liver cells

Question 38

SR-B deficiency

Answer 38

have high concs of chol, lg HDL particles

Question 39

atherosclerosis

Answer 39

16mln w/attack/stroke; fueled by inflam imm response

Question 40

intima

Answer 40

below endothel layer; mainly CT; in healthy, few scattered macs, SM cells, LDL; inflam process occurs here (chol accum, atherosclerosis occurs); LDL particles accum here (LDL transcytoses through endothel layer)

Question 41

mLDL

Answer 41

= OxLDL; macs, endothel, SM cells secrete inflam cytokines; LDL mod initiates atherosclerosis (foamy macs-->coalesce-->plaque)

Question 42

cap formation

Answer 42

atheroma is lipid pool w/foam cells, necrotic cells, free and esterified chol; cap forms on top w/macs, lymphocytes, and SMCs; SMCs sec collagen, elastin, proteoglycans to form fibrous matrix around cap

Question 43

proteases from macs

Answer 43

thin the cap at edges, causing rupture and contents come into contact w/procoag elements in blood-->acute thrombus occluding the lumen; areas exp to blood are platelet adhes sites, sec cytokines that perpetuate process, inc potential for thrombus/clot

Question 44

atheroma w/ or w/o plaque disruption

Answer 44

doesn't nec completely occlude lumen; proc can be repeated mult times; only 20% lumen blocked when rupture takes place to completely block artery, on avg

Question 45

HDL removal of chol

Answer 45

chol can be remv'd from mac foam cells by transport via ACDA1 transporter to HDL (to liver for breakdown); req ApoA; reduces chol conc in plaques (sim to chol removal from periph cells by HDL)

Question 46

LDL driven atheroma resulting in stenosis

Answer 46

usu results in angina, can be detected by stress test/angiogram before attack

Question 47

LDL driven atheroma non-stentotic

Answer 47

not detected by angio/stress test; maj of plaque ruptures occur at areas w/o suff narrowing to be detected; worse b/c no pain, can't detect until attack

Question 48

inc risk of inflam and athero

Answer 48

age, gender, smoking, obesity, T2DM, hypertension/ANG, menopause, high TAGs; other inflam dis like AD, psoriasis, asthma, arthritis, periodontal disease

Question 49

biochem markers for inflam detection

Answer 49

C-reactive prot; synth in liver; 5 monomers of 25000 MW each; adipocytes and macs synth IL6 cytokine, which induces liver to synth CRP; rise in inflam response somewhere (not specific to type of disease); elevated in cardiovasc disease; drop in ppl who exercise, stop smoking, lose weight; plaques less likely to rupture when CRP low; can have bad effect w/low LDL if high CRP