Lightbody Lecture 15 and 16 Flashcards Preview

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Flashcards in Lightbody Lecture 15 and 16 Deck (49):
1

lipoprotein particles

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

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chylomicrons

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

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VLDL

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

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LDL

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

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HDL

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

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apolipoproteins/apoproteins

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)

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Apo A-I

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)

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Apo B 100

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

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Apo B 48

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

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Apo CII

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

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Apo CIII

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

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Apo E

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

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Apo E4

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

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chylomicrons

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

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lipoprotein lipase (LPL)

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

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intermed density lipoprot

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

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lipoprot lipase deficiency

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

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ApoE and Apo B 100 bdg

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

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LDL fxn

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)

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small, dense LDL

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

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HDL

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

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ABCA1-ATP bdg cassette transporter

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

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LCAT (lecithin-chol acyl transferase)

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

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CETP

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

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CETP inhibitors

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

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ApoCIII

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

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HDL

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

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lipoprot receptors

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

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LDLRs

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

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scavenger receptors (SR)

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

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LDLR epidermal GF homology domain

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

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cyto domain of LDLR

50 AAs; cont signal seq for internalization of receptor

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LDLR path and chol reg in liver

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

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excess chol in liver reduced by

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

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familial hypercholesterolemia

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

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SR-A

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)

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SR-B

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

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SR-B deficiency

have high concs of chol, lg HDL particles

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atherosclerosis

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

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intima

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)

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mLDL

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

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cap formation

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

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proteases from macs

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

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atheroma w/ or w/o plaque disruption

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

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HDL removal of chol

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)

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LDL driven atheroma resulting in stenosis

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

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LDL driven atheroma non-stentotic

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

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inc risk of inflam and athero

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

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biochem markers for inflam detection

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