Lipoprotein Metablism

Front 1

apoB-48

Back 1

chylomicrons from SI -> future remnants

Front 2

apoB-100

Back 2

VLDL, IDL, LDL -> all from liver

Front 3

apoA-I

Back 3

HDL

Front 4

apoA-II

Back 4

HDL

Front 5

apoE

Back 5

VLDL, IDL, and HDL; binds LDLR on liver to allow uptake

Front 6

apoC-II

Back 6

chylomicrons and VLDL; activate LPL to allow hydrolysis of TG into FA (after hydrolysis, chylomicrons and VLDL lose apoC-II and gain apoE)

Front 7

LPL

Back 7

lipoprotein lipase -> enzyme on membrane of cardiac/skeletal muscle and adipose, activated by apoC-II, hydrolyzes TG into FA that are taken up by cell

Front 8

exogenous pathway of lipoprotein metab

Back 8

chylomicrons from SI (w/ apoB-48, apoC-II) have apoC-II on their surface, which activates LPL on muscle and adipose; LPL turns TG into FA which are absorbed by tissues; chylomicron remnant (apoB-48, apoE) taken up by liver (LDLR binds apoE)

Front 9

endogenous pathway of lipoprotein metab

Back 9

VLDL (from liver, apoC-II, apoB-100) has apoC-II on its surface, which activates LPL on muscle and adipose; LPL turns TG into FA which are absorbed by tissues; IDL (apoE, apoB100) can either be removed by liver via LDLR-apoE interaction (minor), or can be converted into LDL, which is removed by liver via LDLR-apoB100 interaction (major)

Front 10

lipoprotein disorder class I: name, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 10

FCS; mutations in LPL and apoC-II; high chylomicrons and VLDL (can't be broken down to remnants and IDL); very high TG; eruptive xanthomas; pancreatitis

Front 11

lipoprotein disorder class IIa: name, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 11

FH, FDP, ADH3; mutations in LDLR, apoB-100, PCSK9; high LDL (liver can't uptake); normal TG; tendon xanthomas; CHD

Front 12

lipoprotein disorder class IIb: name, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 12

FCHL; unknown mutation; high LDL and VLDL; mod high TG; no xanthomas; CHD

Front 13

lipoprotein disorder class III: name, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 13

FD; apoE2 mutation; high remnants and IDL (liver can't uptake) w/ low LDL for some unknown reason; mod high TG; palmar tubero-eruptive xanthomas; CHD and PAD

Front 14

lipoprotein disorder class IV: name, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 14

FHTG; unknown mutation; high VLDL; mod high TG; no xanthomas; no clinical seq

Front 15

lipoprotein disorder class V: name, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 15

FHTG; unknown mutation (but prob stops VLDL -> IDL transformation somehow, altho not via mutation in LPL); high VLDL and chylomicrons; very high TG; eruptive xanthomas; pancreatitis

Front 16

eruptive xanthomas

Back 16

class I (FCS) and class V (FHTG) lipoprot disorders

Front 17

palmar tubero-eruptive xanthomas

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class III (FD)

Front 18

tendon xanthomas

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class IIa (FH)

Front 19

mutation in LPL

Back 19

FCS (class I)

Front 20

mutation in apoCII

Back 20

FCS (class I)

Front 21

mutation in LDLR

Back 21

FH (class IIa)

Front 22

mutation in apoB100

Back 22

FDP (class IIa)

Front 23

mutation in PCSK9

Back 23

ADH3 (class IIa)

Front 24

mutation in apoE2

Back 24

FD (class III)

Front 25

pancreatitis caused by what lipo disorder (2)

Back 25

class I (FCS), class V (FHTG)

Front 26

CHD caused by what lipo disorder (3)

Back 26

class IIa (FH), class IIb (FCHL), class III (FD)

Front 27

secondary causes of hyperlipoproteinemia (7)

Back 27

more common than primary (aka genetic): diet, alcohol use, insulin resistance/T2DM, hypothyroidism, nephrotic syndrome, chronic renal failure, meds

Front 28

family chylomicronemia syndrome: class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 28

FCS (class I); mutations in LPL and apoC-II; high chylomicrons and VLDL (can't be broken down to remnants and IDL -> makes blood white); very high TG; eruptive xanthomas; pancreatitis

Front 29

familial dysbetalipoproteinemia: class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 29

FD (class III); apoE2 mutation (not 100% penetrant tho -> need environmental influence); high remnants and IDL (liver can't uptake) w/ low LDL for some unknown reason; mod high TG; palmar tubero-eruptive xanthomas; CHD and PAD

Front 30

apoE alleles (3)

Back 30

apoE3 is normal; apoE4 is correlated w/ Alzheimer's (25% people carry at least one allele); apoE2 causes FD (class III) when homozygous (not 100% penetrant though -> needs environmental hit)

Front 31

family hypercholesterolemia: class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 31

FH (class IIa); mutation in LDLR; high LDL (liver can't uptake); normal TG; tendon xanthomas; CHD

Front 32

familial defective apoB100: class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 32

FDB (class IIa); mutation in apoB100; high LDL (liver can't uptake); normal TG; tendon xanthomas; CHD

Front 33

autosomal dominant hypercholesterolemia 3: class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 33

ADH3 (class IIa); GOF mutation in PCSK9; high LDL (liver can't uptake b/c LDLR downregulated by PCSK9); normal TG; tendon xanthomas; CHD

Front 34

PCSK9

Back 34

normally downregulates LDLR; when mutated in ADH3 (class IIa) it causes a gain of function that leads to extreme downregulation (no LDLR, so LDL remains in blood); novel therapy against LDL works by inhibiting PCSK9

Front 35

familial hypertriglyceridemia: class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 35

FHTG (class IV or V -> pts begin in type IV, which is asymptomatic, and a second hit like poor diet leads to type V, which has sx that resemble type I aka FH); unknown mutation (blocks VLDL -> IDL conversion, but not via LPL mutation) -> some pts may have genetic mutation, some may be due to alcohol or insulin resistance; high VLDL and chylomicrons w/ normal LDL; very high TG; eruptive xanthomas; pancreatitis

Front 36

familial combined hyperlipidemia class, etiology, which lipoprotein is elevated, are TGs elevated, xanthomas, clinical seq

Back 36

FCHL (class IIb); unknown mutation; high LDL, VLDL, TG (apoB very elevated) due to overproduction of VLDL (like in T2DM, except these pts are not insulin resistant); mod high TG; no xanthomas; CHD

Front 37

lipo(a)

Back 37

independent risk factor for CHD; highly genetically determined; lipo(a) looks like LDL (apoB100, similar density), but w/ apo(a) attached, which resembles plasminogen

Front 38

HDL structure and apo proteins

Back 38

small, dense, w/ apoA-I (major) and apoA-II (minor); liver and SI both produce A-1 while only liver produces A-2

Front 39

ABCA-1

Back 39

takes cholesterol from macrophages -> nascent HDL

Front 40

CETP

Back 40

siphons cholesterol from HDL to VLDL/LDL in exchange for TGs; if CETP is inhibited, HDL is high, however CHD is also incr (is the incr HDL the "right" HDL?)

Front 41

secondary causes of low HDL (6)

Back 41

very low fat diet; sedentary lifestyle; obesity; insulin resistance/T2DM; chronic renal failure; meds

Front 42

primary (genetic) causes of low HDL (3)

Back 42

apoA-I mutations, Tangier disease (ABCA1 mutations), LCAT deficiency

Front 43

Tangier disease

Back 43

ABCA1 mutation -> low HDL (can't transfer chol from macrophages to nascent HDL)

Front 44

LCAT

Back 44

turns nascent HDL into mature HDL by esterifying free cholesterol and thus making it insoluble and stuck in center of HDL

Front 45

milky corneas seen in

Back 45

LCAT deficiency -> free cholesterol builds up in cornea

Front 46

standard dietary recommendation to lose weight

Back 46

reduce intake by 500-1000 Cal/day to lose .5-1 kg/week

Front 47

calories per gram in diff food types

Back 47

protein and carbs are 4 cals/gram; fat is 9 cal/gram

Front 48

very low fat diets: clinical study results

Back 48

changes in fat COMPOSITION, not quantity, led to red in CHD events

Front 49

low fat vs low carb diet: weight, LDL, TG

Back 49

low carb diet decr TG at 1 yr, decr weight at 6 mos (but not at 1 yr); low fat diet decr LDL at 1 yr

Front 50

best diet for CHD health

Back 50

Mediterranean diet -> better weight loss, decr cholesterol most, decr cardiac death

Front 51

absorption of dietary steorls

Back 51

more carbon atoms and desaturation = lower absorption rate (we don't absorb plant sterols = good for you)

Front 52

cholesterol in intestine: where does it come from, how much is absorbed?

Back 52

75% from bile, 25% from food; 50% is absorbed, 50% lost in feces

Front 53

daily cholesterol synthesis amount and location, diet amount

Back 53

1.2 g/day synthesized (10% liver, 90% elsewhere), .4 g/day eaten

Front 54

fructose and disease

Back 54

incr caloric intake -> obesity; causes insulin resistance; causes dyslipidemia (some fructose converted to FA)

Front 55

exercise dose

Back 55

total amount of energy expended

Front 56

absolute vs relative exercise intensity

Back 56

absolute = rate of energy expenditure (expressed in METs); relative: % of max aeorbic power (% of max HR or VO2) ---> 40-60% VO2max gen considered "moderate intensity"

Front 57

goal in increasing fitness in atherosclerosis

Back 57

moderate fitness group has large decr in CVD risk compared to sedentary group -> getting people to walk 150 min/week is a huge improvement; more important to be fit than to be normal weight (fitness is independent risk factor from BMI)

Front 58

exercise and platelets

Back 58

short term exercise can lead to incr platelet activity (esp in sedentary pts); but long-term exercise may abolish or reduce response

Front 59

physical activity goal

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30 mins 7 days/week, or at least 5 days/week

Front 60

TG levels

Back 60

normal <150; risk for pancreatitis >500 (and thus tx to lower TG); 150-500 at risk for CHD, but no data supports lowering TG to alleviate risk

Front 61

non-HDL target

Back 61

30 mg/dL higher than LDL target

Front 62

LDL goals (3)

Back 62

less than 100 (<70 ideal) if CHD or CHD risk equiv (diabetes, etc.), <130 (<100 ideal) if 2+ risk factors, <160 if 0-1 risk factors

Front 63

low HDL definition

Back 63

<40 mg/dL

Front 64

drugs used to tx dyslipidemia (6)

Back 64

reduce LDL: statins, cholesterol absorption inhibitors (ezetimibe, plant sterols), bile acid sequestrants (resins); tx TG/HDL axis: fibrates, niacin, fish oils (omega 3)

Front 65

NPC1L1

Back 65

transports intestinal cholesterol into enterocyte

Front 66

ABCG5/G8

Back 66

pumps cholesterol out of enterocyte into intestinal lumen

Front 67

IBAT

Back 67

reabsorbs bile salts in terminal ileum

Front 68

the rule of 6%

Back 68

each doubling of dose of statin produces 6% decrease in LDL; starting dose accomplishes majority of reduction (20-40%), with full titration giving 30-60%

Front 69

adverse effects of statins (2)

Back 69

high hepatic transaminases, muscle related adverse effects (myalgia, myopathy, rhabdomyolysis)

Front 70

myalgia vs myopathy vs rhabdomyolysis

Back 70

myalgia is ache/weakness w/o CK elev; myopathy is weakness w/ incr CK; rhabdomyolysis in weakness w/ incr CK and incr creatine

Front 71

ezetimibe: mechanism (2), when to use, adverse effects

Back 71

inhibits NPC1L1 and thus chol absorption from SI -> reduces chol stores and thus results in LDLR upregulation (most imp. mech); use 2nd line after statin; side effects = elevated transaminases

Front 72

resins: what are they, examples (3), adverse effects (4)

Back 72

bile acid sequestrants; cholestyramine, colestipol, colesevalem; not absorbed so thus lack systemic toxicity, however they do cause GI sx (constipation, bloating, flatulence, heartburn, nausea), can interfere w/ drug absorption, and can raise TG levels

Front 73

cholesytramine

Back 73

resin (bile acid sequestrant)

Front 74

colestipol

Back 74

resin (bile acid sequestrant)

Front 75

colesevalem

Back 75

resin (bile acid sequestrant)

Front 76

fibric acid derivs: mech, results (2), indications for use (2), examples (3)

Back 76

activates PPARalpha (TF) -> incr LPL activity (via altering apo CIII:CII ratio) and thus decr TG and VLDL;, also incr HDL prod by incr apoA synthesis and by incr ABCA1; results: HDL incr 5-20%, TG decr 20-50% (main effect on TG); indications: TG > 500 to prevent pancreatitis, or adjunct to statin in pts w/ elevated TG; egs: clofibrate, gemfibrozil, fenofibrate

Front 77

clofibrate

Back 77

fibric acid derivs

Front 78

gemfibrozil

Back 78

fibric acid derivs

Front 79

fenofibrate

Back 79

fibric acid derivs

Front 80

PPARalpha

Back 80

TF activated by fibrates; causes incr LPL activity by altering CIII:CII ratio (incr it) and thus decr TG (incr clearance) and VLDL (incr catabolism); also incr HDL by incr apoA and ABCA1

Front 81

fibrates adverse effects (5)

Back 81

normally well tolerated; incr in liver transaminases can occur rarely; can cause mylagia/myopathy; can potentiate action of oral anticoagulants; statin blood levels incr (only w/ gemfibrozil)

Front 82

niacin: what is it, how does it work, results (4), side effects (6)

Back 82

niotinic acid aka niacin aka vitamin B3; use in high doses (higher than vitamin dosage) to reduce FFA release from adipose (acts through receptor GPR109A); results: incr HDl 25%, decr TG 30%, decr LDL 20%, decr Lp(a) 22% -- best drug to raise HDL; side effects: flushing (due to incr prostaglandins), gout made worse, high dose hepatotoxicity, rarely hypophosphatemia and reduced platelets, exacerbates insulin resist in T2DM

Front 83

GPR109A

Back 83

receptor on adipose that niacin binds to in order to prevent FFA efflux

Front 84

best drug to lower high TG

Back 84

fibric acid derivs, omega 3s

Front 85

best drug to raise HDL

Back 85

niacin

Front 86

best drug to lower LDL

Back 86

statins

Front 87

omega-3 fatty acids: egs (2), results (1), use (1)

Back 87

EPA and DHA; decr TG by 40%; use in pts w/ TG > 500 to prevent pancreatitis

Front 88

novel therapies against LDL

Back 88

inhibition of PCSK9; antisense oligonucleotide to apoB; MTP inhibition

Front 89

MTP

Back 89

enzyme necessary to form VLDL from TG and apoB; inhibition of MTP may lead to lower LDL