Lipoproteins - Abali 2/19/16 Flashcards

Question

classification of lipoproteins

Answer 1

placed into general classes on basis of * electrophoretic mobility * density * tissue of origin * average composition of lipoprotein broad particle classes: **chylomicron, VLDL, LDL, HDL**

Answer 2

**chylomicrons** * lowest density, largest size. * highest % lipid, lowest % protein. *_progression moving down list:_ more dense, higher protein:lipid ratio* VLDL LDL HDL

Answer 3

**1. processing**: changes in composition of surgace and core components during transit : _conversion to *remnant form*_ **2. clearance from blood**: in liver and other tissues via _receptor-mediated endocytosis_

Answer 4

* several fx (ex. recognition sites for receptors, acrivators/coenzymes of metabolic enzymes), but not all fx are known * some are req structural components of lipoproteins, others are transferred freely between liproporteins * **divided by structure and fx into 5 major classes: A, B, C, D, E** * most classes have subclasses (I, II, etc)

Answer 5

* _source_: intestine * _fx_: transport of **dietary TAG** * _major apolipoproteins_: B48, CII, CIII, E

Answer 6

* _source_: liver * _fx_: transport of **endogenously synth'd TAG** * _major apolipoproteins_: B100, CII, CIII, E

Answer 7

* _source_: formed in circ by partial brakdown of IDL * _fx_: delivers cholesterol to periph tissues * _major apolipoproteins_: B100

Answer 8

* _source_: liver * _fx_: removed "used" chol from tissues and takes it to liver (**reverse transport**) * "reservoir" for apoproteins donated from other lipoproteins * _major apolipoproteins_: AI, AII, CII, CIII, E

Answer 9

**1. exogenous pathway:** originates in intestine, involves dietary lipids (in chylomicrons) **2. endogenous pathway:** originates in liver, involves mostly de novo synthesized lipids (in VLDL, LDL, IDL) **3. reverse cholesterol transport pathway:** deals largely with cholesterol (in HDL) from peripheral tissues

Answer 10

TAG → FAs + glycerol 1. lipoprotein lipase 2. hepatic lipase

Answer 11

"reservoir" = HDL * holds, loses, regains apoCII, apoCIII, apoE as needed **1. apo CII:** lipoprotein lipase activator (essential cofactor for LPL) * synth in liver, held on HDL * essential cofactor for lipoprotein lipase (key for reducing TAG content, changing TAG:CE ratio of anhydrous core, altering particle shape) **2. apo CIII:** lipoprotein lipase inhibitor **3. apo E:** ligand for receptor-mediated clearance of chylomicrons by liver * synth in liver, picked up from HDL by chylomicrons * once on chylomicron remnants (and/or VLDL/IDL remnants), binds to **LRP1** (LDL receptor-related protein 1) on hepatocytes * remnants undergo endocytosis

Answer 12

**cleaves FAs from TAGs in anhydrous core of lipoproteins [cofactor: apoCII on CM, VLDL)** * drops TAG content (changes TAG:CE ratio) * alters particle shape _what happens to liberated FAs?_ * can be taken up by adipose for storage in resynth'd TAGs * can be taken to metabolically active periph tissues for use as energy

Answer 13

**lipoprotein lipase activator (essential cofactor for LPL)** * synth in liver, held on HDL * essential cofactor for lipoprotein lipase (key for reducing TAG content, changing TAG:CE ratio of anhydrous core, altering particle shape)

Answer 14

**lipoprotein lipase inhibitor**

Answer 15

**ligand for receptor-mediated clearance of chylomicrons by liver** * synth in liver, picked up from HDL by chylomicrons * once on chylomicron remnants (and/or VLDL/IDL remnants), binds to LRP1 (LDL receptor-related protein 1) on hepatocytes * remnants undergo endocytosis

Answer 16

**_location_**: attached to endothelial cells in blood cap walls via interaction with GAGs **_fx_**: acts on chylomicrons and VLDLs, catalyzes hydrolysis of **TAGs → FAs + glycerol** * _cofactor_: apoCII (on lipoprotein) **_product fates:_** 80% taken up, 20% shuttled back to liver indirectly * *if immediately taken up*: stored (adipose), used (muscle, heart) * *if not*: long chain FAs are transported by serum albumin until taken up

Answer 17

**_source/location_**: synth in hepatocytes * primarily found on liver endothelial cells, HSPG (heparin sulfate proteoglycan) in space of Disse * transported from liver to cap endothelium of adrenals, ovaries, testes : releases lipids from lipoproteins for use **_fx_**: phospholipase (also has triglyceride hydrolase activity) * final CM processing: hydrolyzes triglycerides, excess surface PL * completes IDL→LDL processing * helps convert HDL2→HDL3 (removes triglyceride and phospholipid from HDL2)

Answer 18

* sourced from foods derived from animals only _processing_ * **intestinal lumen:** cholesteryl esters are hydrolyzed, chol and other sterols are packaged → **mixed micelles** containing bile salts, fatty acids, monoglycerides * **jejunum:** epithelial cells pick up via indiscriminate binding to **NPC1L1** (Niemann-Pick C1-Like protein 1) : most sterols expelled, chol retained * **intestinal epithelial cells:** use **MTP** (microsomal triglyceride transfer protein) to assemble CM from apoB48 + **_TAG_** + PL + C + CM * **transit to liver:** CM exported into lymphatic system : thoracic duct to subclavian vein * **in blood:** pick up apoCII (LPL cofactor) and apoE (needed for CM remnant endocytosis) - mostly from HDL * **in blood:** LPL (on endothelial surface) removes TAGs [cofactor: apoCII] * CM remnant dissociates from LPL, return apoCII to HDL * **into liver:** CM remnants enter space of Disse, where **HL** (hepatic lipase) removes more TAGs. * ******apoE binds to LRP1** (LDL receptor-related protein 1) on hepatyctes → endocytosis. * **in liver**: lysosomes degrade CM remnants * dietary chol either repackaged in VLDLs and sent out _or_ converted to bile salts * dietary chol inhibits liver chol synth

Answer 19

A, D, E, K absorbed in small intestine, transported with CM to liver

Answer 20

total TG = TG inside all lipoproteins (CM, CM remnants, VLDL, IDL, LDL, HDL) fasting blood sample = VLDL, IDL, LDL, HDL * CM clearance t_1/2 after meal = minutes, so fasting blood sample is taken to **avoid contamination by CM and CM remnants** * after overnight fast, very little CM and CM remnants in blood

Answer 21

* VLDL synthesized in liver from FAs * some FA synth by liver from excess carbs, lots received on blood * FAs esterified into TAGs → TAGs packaged into VLDLs → VLDLs released into blood (t_1/2 = hours) * nascent VLDL contains apoB100, apoE, apoCII * additional apoE and apoCII donated from HDL * **apoCII** is cofactor for _LDL : degrades TAGs in VLDL and delivers liver-origin FAs to adipose and other tissues_ * LPL action on VLDL → VLDL remnant (aka IDL) * **apoE** is ligand for LRP1 receptor : 50% IDL moves into liver * rest of IDL converted to LDL (with B100)

Answer 22

VLDL remnants = IDL (with apoE, apoB100) : _TAG transport_ and _LDL precursor_ * approx 50% IDL removed from circ via apoE-LRP1/endocytosis * other 50% IDL converted to LDL, stay in circ * LPL and HL (hepatic lipase) remove TAGs and PLs → enrich CE content during processing into LDL

Answer 23

LDL (with B100) : cholesterol transport (major carrier in blood) and delivery * apoB100 acts as ligand for LDL receptors in cells throughout body ("unlocks doors" in cells for chol delivery) * LDL t_1/2 = days, so comprises most of what you see in a fasting sample

Answer 24

* **2/3 of LDL** in circ taken up by _**liver** via apoB100 binding to LDL receptor_ * **1/3 of LDL** taken up by _**peripheral tissues** (mostly) via apoB100 binding to LDL receptor_ * significant source of chol for peripheral tissues (supplement endog synth) \*LDL receptor (and apoB100 binding) is not the only means of LDL clearance from blood!

Answer 25

hepatocytes and periph cells display LDL receptors **based on their need for chol** * SREBP2 senses chol in ER membrane and upregulates LDL receptor synth (or not) * once LDL is endocytosed, **lysosomal acid lipase** hydrolyzes TAG and CE in lysosomes * LDL receptors can be recycled back into pl membrane to repeat **regulation** (key part of chol-dependent LDL receptor # reg) * liver secretes **enzyme PCSK9** into blood, signals LDL receptors _not to recycle to pl mem; favors lysosomal degradation_

Answer 26

**macrophases and some endothelial cell types possess SR-A (scavenger receptor)** * **SR-A**: lower affinity (for LDL), but broader specificity (can bind normal and damaged LDL) * greater affinity for oxidized/damaged LDL * endocytosed particles taken to lysosome : free cholesterol released into cytosol accounts for good chunks of LDL uptake in intestine and spleen

Answer 27

* VLDL syntehsized in liver with apoB100, apoCII and apoE from HDL * VLDL moves through circ until it associates with LPL [cofactor: apoCII] : TAG hydrolyzed, FA liberated to local tissues (stored as fat/used as egy) : VLDL shrinks → IDL → LDL (apoCII returned to HDL) * some LDL heads back to liver (via apoE), some LDL returns apoE to HDL and hits extrahepatic tissues via LDL-receptor and SR-A LDL is the route through which chol is transported from liver to tissues (supplements small amt of endog synth chol)

Answer 28

**case of differential post-translational mRNA editing** * *apoB mRNA* is made in liver and small intestine * in sm int **only**, CAA (Glu) C deaminated → U * **intestine** makes a truncated version of the transcript, **apoB48** - _incorp into chylomicrons_ * **liver** makes full-length version of transcript, **apoB100** - _incorp into VLDL_

Answer 29

**removes excess chol from peripheral tissues and returns it to liver (body's chol "clearinghouse") via HDL** chol from liver → tissues: chol transport chol from tissues → liver, then: reverse chol transport * **liver:** makes apoAI (LCAT activator), secreted into blood * **in blood:** lipid + apoAI = HDL (apoAI is signature HDL protein, makes up 70% of apoprotein in HDL) * **later on in blood: +** apoAII (activator of HL), apoCII, apoCIII, apoE **_fx_** * circulating reservoir of apolipoproteins * _apoCII_ - cofactor for LPL * _apoE_ - ligand for receptormediated endo of remnants (VLDL remnants/IDLS and CM remnants)

Answer 30

**cholesterol ester transfer protein** * secreted from liver, circulates in plasma (bound mainly to HDL) * promotes redistribution of CE, TG, and PL (to lesser extent) between pl lipoproteins * overall effect: net mass transfer of... * **CE: from HDL to VLDL** * **TG: from VLDL to HDL****** * _reduction in HDL size/chol content : "remodeling"_ following CETP action, HP removes TGs from HDL

Answer 31

**1. liver/intestine:** apoAI + PL + C = _nascent HDL_ * _key apoprotein_: apoAI to start * poorly lipidated: PL (phosphatidylcholine) and C * apoAII, apoE, apoCs aquired later in circ * disc shaped **2. ABC A1** (ATP-Binding Cassette transporter A1) enriches HDL with PL (phosphatidylcholine) and C [both from pl mem] → _discoidal nascent HDL_ **3.** C loaded onto HDL is immediately esterified by **LCAT** [transfers FA from phosphatidylcholine to C; cofactor: apoAI] → more hydrophobic CE (sequestered in anhydrous core) * discoidal nascent HDL picks up more CE via LCAT → relatively _CE-poor HDL3_ → relatively _CE-rich HDL2_ * CETP pulls the CE/TG swap between HDL/VLDL : keeps product inhibition of LCAT off * VLDLs are catabolized to LDL → CEs on VLDL ultimately taken up by liver! **4.** CE taken up by liver via **SR-B1** (scavenger receptor B1) which binds HDL : selective uptake of CE from HDL particle * **HL** (since it can degrade TG and PL) helps convert HDL2 → HDL3 [activated by apoAII] **5.** ultimately, HDL is degraded by liver * chol either excreted in bile salts **or** repackaged in VLDL for distribution to tissues

Answer 32

regulated based on... * chol arriving through HDL * brought from periph cells, which add it to HDL * dietary chol returned by CM remnants

Answer 33

**coronary artery disease** * leading cause of natural death in the world * correlated with levels of plasma chol/TG-containing particles * steady state levels in circ can be influenced by... * genetic factors * diet * obesity

Answer 34

either primary or secondary * **primary**: can result from single inherited gene defect or combo of genetic and environmental factors * **secondary**: result of metabolic disorder (DM, obesity, hypothyroidism, 1 biliary cirrhosis) _tx strategies_: dietary intervention + drugs

Answer 35

**total fasting pl TG \> 150 mg/dl** due to abnormally high CM, VLDL, or both (either formed at high rate or removed at low rate) * USA: 1/3 of adult pop has it, 0.2% has severe/v severe * _risks_ * __increased risk for CVD * v severe hyper TGemia * pancreatitis * eruptive and tuberous xanthomas * _risk factors:_ * insulin resistance (obese/DM2), hypothyroidism, alcoholism, meds, pregnancy, genetic predisp

Answer 36

**lipoprotein lipase deficiency** or **apoCII deficiency** * **pathologic presence of chylomicrons after 12-14h fasting [fasting TG \> 1000 mg/dl]** * creamy supnernatant when refrigerated * _features_: eruptive xanthomata, lipemia retinalis, hepatosplenomegaly, focal neurologic symptoms (ex. irritability), recurrent epigastric pain with increased risk of pancreatitis * key distinguishing features * initial manifestation during childhood * biochemically-demonstrated deficiency of LPL (or homozygous gene muts), apoCII * low population prevalence (1/10M)

Answer 37

**manifestation** * FC: initial manifestation during childhood * PMH: adulthood **function issue** * FC: biochemically-demonstrated deficiency of LPL, apoCII, or homozygous gene muts * PMH: less severefx deficits, infrequent detection of gene mut **prevalence** * FC: low population prevalence (1/10M) * PMH: more prevalent (1/1K) **extras**: PMH has secondary factors more often and shows a greater elevation of total chol

Answer 38

**drop food intake** : reduces production of CM (from dietary TG) and VLDL (from dietary TG and de novo synth from carbs) * dropping pl TG \< 500 mg/dl virtually eliminates repeat risk of hyperTGemia-induced pancreatitis

Answer 39

dys (bad) beta (B100) **apoE deficiency** * overproduction or underutilization of IDL : **increased IDL → increased TG (250-400) and chol (250-400)** * ****also see elevated plasma LDL (due to interrupted processing of VLDL) * _prevalence_: 1-2/20K * _features_: **xanthomas, accelerated coronary and periph vascular disease by middle age** * tuberous or tuberoeruptive xanthomata on extensor surfaces of extremities * planar or palmarcrease xanthomata * increased risk of CVD * typically homozygotic for binding-defective apoE * phenotypic expression usually requires: obesity, DM2, hypothyroidism * _diagnosis_ * increased VLDL-C:TG ratio * apoE homozygosity

Answer 40

**defects in synthesis, processing, or fx of LDL receptors** * relatively common: prevalence 2-5% * autosomal dom with variable penetrance * increased VLDL and LDL, decreased HDL * VLDL increased → elevated serum TAG (500) and C * excess TAG in liver/sm int can cause overproduction and delayed lipolysis of VLDLs and CMs * increased CETP activity! * increased CETP activity leads to rapid formation of small LDL particles → also high levels of small HDL particles * see high LDL levels in these pts * small HDL are renally excreted: see low HDL, apoAI levels in these pts

Answer 41

1. lifestyle mods * weight loss, exercise, diest low in sat FAs, avoding excess alcohol 2. drugs to normalize pl TAG * diabetes? wt control via exog **insulin** * hypothyroidism? **levothyroxine** * **statin**: drops VLDL production * **fibrate**: activate PPARalpha tfs → increasedLPL activity, increased rate of FA beta-ox * **nicotinic acid** (niacin/vitB3): activates niacin receptor 1 → inhibits lipolysis and release of FAs from adipose tissue

Answer 42

**v high levels of chol in blood** * high risk of developing CAD due to devpt of atherosclerosis * buildup in other tissues: **xanthomas** contain chol-laden foam cells (location dependent on dylipidemia cause) * hyperchol with no hyperTG : **tendon xanthomas** (Achilles tendons and tendons in hands/fingers) * hyperchol with hyperTG : tuberous xanthoma (over joints) * under skin (ex. eyelids): **xanthelasma**

Answer 43

1. formation of fatty streak 2. streak becomes altered to fibrous plaque 3. plaque becomes altered to complicated lesion **fatty streak formation** * recruitment of monocyte macrophages to subendothelial space, infiltration of oxidized LDLs * oxidized LDLs picked up by macrophages → foam cells → release cytokines and growth factors, leading to more infiltration, new cell division → fatty streak! (normal: form/spontaneously dissolve) **progression to fatty streak lesion** * further recruitment of monocyte-macrophages from plasma, sm muscle proliferation, collagen synth. elastin fibers begin to accumulate **progression to fibrous lesion** * lesion beings to extend into lumen. necrosis of foam cells, migration of smooth muscle cells through, some of which accumulate lipid droplets **progression to complicated lesion** * endothelial cell layer covering lesion lost → surface becomes thrombogenic, throbus forms. cellular debris, calcification, chol crystals form can lead to complete occlusion (infarction) or disruption of plaque and thrombosis at distant site (stroke)

Answer 44

highly-heritable independent, causal risk factor for atherosclerosis/ MI * circulating abnormal variant of LDL * Lp(a) is a lipoprotein made of: **apo(a) molecule** covalently linked by **disulfide bond** to **apoB100** * certain SNPs of LPA gene might have higher CV risk levels

Answer 45

**defects in synthesis, processing, fx of LDL receptors** * block in LDL degradation → elevated LDL with normal VLDL levels * increased serum chol (\>400) but normal TGs * ischemic heart disease greatly accelerated _homozygous familial hypercholesterolemia_ * low prevalence: 1/1M * usually two alleles for defective **LDL-receptor** * sometimes homozygous loss of fx muts for **apoB100** * usually 10x lDL chol and without treatment, heart attacks in teens/twenties _heterozygous familial hypercholesterolemia_ * most have mutant allele for **LDL receptor** * 5% mutant **apoB100** * 2% overactive **PCSK9** * usually 2x LDL chol and without treatment, CAD before late 50s

Answer 46

**complete loss of plasma apoAI, normal levels of LDL and TAG** * HDL collection/reverse transport of chol is interrupted bc you cant make normal HDL * nonesterified chol is randomly deposited in excess (ex. cornea, vessels) * _features_: xanthomas, mild to moderate corneal opacification/clouding _why is low HDL a bad thing?_ * low HDL is most common lipoprotein abnormality among pts with CAD, component trait of metabolic syndrome * most common genetic disorder: hypoalphalipoproteinemia (FHA) - HDL levels below 10th percentile and FHx of low HDL

Answer 47

complete deficiency = familial LCAT partial deficiency = fish-eye disease **reduced HDL, reduced apoAI, elevated TAGs, decreased LDL** * free chol greatly increased in plasma and periph tissues because it cant be converted to CE → inability to form mature HDL particles * _features_: early onset corneal opacifications (v striking)

Answer 48

**ABCA1 deficiency** **autosomal recessive, loss of fx muts in ABCA1** * impaired ABCA1 : cant make mature HDL → cant pick up chol from tissues and bring it to liver → chol accumulation in tissues * _features:_ enlarged orange tonsils, hepatomegaly, splenomegaly, occasionally mild corneal opacification fd

Answer 49

* statins are competitive inhibitors of HMG CoA reductase * reduces de novo synthesis of chol in liver * prompts liver to upregulate LDL receptors on hepatocytes * decreased de novo synth + increased efficiency of LDL uptake from plasma = normalized liver chol + lowered plasma chol

Answer 50

inhibits absorption of dietary chol in intestine * competitive inhibitor of Niemann-Pick C1-like 1 protein in brush border cells (involved in chol abs) * stimulates upregulation of liver LDL receptor expression

Answer 51

* increases shunting of chol and bile acids into feces * resins act as binding agents in intestine to sequester bile acids from normal reabs via enterohepatic circ * accelerated loss of bile → liver taps into pool of chol to make more * liver looks to restore chol by increasing de novo synthesis and increaseing LDL receptor expression → decrease in plasma LDL

Answer 52

**inhibits mobilization of FFA from periph adipose tissue to the liver** can lower plasma TG, raise plasma HDL, drop plasma LDL

Answer 53

**activate PPARalpha tfs → increased LPL activity** (+ apoAI, apoAII, - apoCIII *inhibitor of lipolysis*) and **increased rate of FA beta-ox**

Lipoproteins - Abali 2/19/16 Flashcards

(78 cards)