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Molecular and Cellular Princples of Medicine > Unit 6 - Blood Lipoproteins > Flashcards

Unit 6 - Blood Lipoproteins Flashcards

1
Q

what is the main job of lipoproteins?

A

protect hydrophobic cargo from aqueous environment while shuttling them from tissue to tissue

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2
Q

overall structure of lipoproteins

A

inner hydrophobic core of TAG and cholesterol esters, surrounded by shell with amphipathic PL, unesterified cholesterol, and apoproteins
-TAG and cholesterol are from diet or de novo

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3
Q

how do size and density of blood lipoproteins differ?

A

largest chylomicron (lowest density from TAGs)
smallest HDLs (highest density)
-density is PRO:lipid ratio
-also separated based on electrophoretic mobility, or based on their density by ultracentrifugation

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4
Q

how do lipoproteins separate in ultracentrifugation and electrophoresis?

A

top (+) to bottom (-)

  • chylomicron
  • LDL (beta-lipoprotein)
  • VLDL (pre-beta-lipoprotein), chylomicron remnants
  • IDL
  • LDL
  • HDL2 (alpha-lipoprotein)
  • HDL3
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5
Q

what are the functions of apolipoproteins?

A
  • provide recognition sites for cell surface receptors
  • serve as activators for enzymes involved in lipoprotein metabolism
  • required structural components of lipoprotein
  • transferred between lipoproteins
  • divided based on structures and function, into classes denoted by letters, and subclasses of roman numerals
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6
Q

Apo AI

  • where is it synthesized?
  • what does it do?
A

most abundant (structural) apo-LP in HDL

  • made by liver and intestine
  • activates LCAT
  • involved in RCT (reverse cholesterol transport)
  • ligand for ABCA1 and SR-B1
  • considered an antiatherogenic PRO, but genetic defects not always associated with CVD
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7
Q

Apo AII

  • where is it synthesized?
  • what does it do?
A

made mostly in liver

  • present with AI in some HDL (especially HDL3)
  • activates LPL and inhibits LCAT
  • may be proatherogenic
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8
Q

what does LCAT do? what is it activated by?

A

lecithin cholesterol acyltransferase activated by apo AI

  • transfers FA from C2 of phosphotidylcholine/lecithin to cholesterol to make CE and lysoPC
  • involved in maturation of HDL
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9
Q

what is RCT?

A

reverse cholesterol transport

  • transfer of peripheral tissue cholesterol by ABCA1 to nascent HDL
  • esterified by LCAT
  • delivery of CE and free cholesterol on HDL-2 to hepatocytes thru SR-B1 (selective for CE from HDL) for hormone/bile salt/acid synthesis or disposal via bile
  • release of HDL-3 (depleted of lipids)
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10
Q

Apo B-100

  • where is it synthesized?
  • what does it do?
A

made in liver

-binds to lipids made by MTP (microsomal triglyceride transport protein) to make VLDL, and stays for IDL and LDL

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11
Q

what do measurements of Apo B-100 mean?

A

in plasma, it reflects particle number

-higher levels associated with CVD

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12
Q

Apo B-48

  • where is it synthesized?
  • what does it do?
A

made in intestine (48% of B-100 from N-terminal; truncated)

  • involved in chylomicron metabolism
  • not recognized by LDL receptor
  • post-transcriptional editing creats a stop codon
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13
Q

Apo CI - III

  • where is it synthesized?
  • what does it do?
A

all made in liver

  • exchanged freely among lipoproteins
  • important for TG metabolism, b/c interfere w/ recognition of apo E by lipoprotein receptors, or displace apo E from lipoproteins
  • I activates LCAT
  • II activates LPL
  • III inhibits LPL
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14
Q

apo E

  • where is it synthesized?
  • what does it do?
A

made in liver, and associated with all LPs except LDL

  • yet somehow recognized by LDL receptor and LRP (LDL receptor-related PRO, also remnant receptor) to mediate hepatic uptake of chylomicrons and VLDL remnants, plus IDL
  • primarily responsible for clearance of intestinal-derived LPs after a meal, and clearance of VLDL and IDL before converted to LDL
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15
Q

what are the 3 isoforms of apo E?

A

2 - least common; risk factor for dysbetalipoproteinemia (type III hyperlipidemia) characterized by elevated chylomicron and VLDL remnants in plasma
-binds poorly to receptors
3 - most common, and “normal” variant
4 - associated with Alzheimer’s disease (increased susceptibility and lower age of onset)

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16
Q

where does chylomicron metabolism occur and what does it do?

A

assembled in intestinal mucosal cells

-carries dietary TAG, choelsterol, ADEK, and cholesterol esters to peripheral tissues

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17
Q

what are the 5 steps of chylomicron metabolism?

A
  1. B-48 (unique to chylo) made and glycosylated in intestinal mucosal cells, and MTP loads it with dietary lipid (TAG)
    - transferred from ER to Golgi, and packaged in secretory vesicles, that fuse with plasma membrane to release nascent chylomicron, which enters lymphatic system, then blood
  2. when nascent chylomicron reaches blood, it gets apo E (recognizes hepatic receptors) and apo C (including II from HDL)
  3. LPL (attached by heparin sulfate to capillary walls) is activated by CII to hydrolyze TAG and make FA and glycerol
    - FA stored in adipose tissue, or used for energy in muscle
    - glycerol used by liver for lipid synthesis or gluconeogenesis
  4. particle decreases size, increases density and returns apo C(II) to HDL to make chylomicron remnant
  5. CR taken up by liver by apo E binding to specific LPR, followed by endocytosis
    - lysosomal hydrolytic enzymes degrade to cholesterol, AA, and FA, and receptors are recycled
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18
Q

what is lipoprotein lipase? how does it work?

A

LPL is anti-parallel homodimer

  • each subunit has N-terminal domain with lipolytic site, and C-terminal domain that binds to particle with substrate specificity to CII
  • after binding to CII, a lid moves away from lipoprotein so that TAG can be degraded
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19
Q

LPL expression in fed VS fasted

A

fed: increased in adipose, decreased in muscle
fasted: increased in muscle, decreased in adipose

20
Q

what happens if people have deficiency of LPL or apo CII?

A

type I hyperlipoproteinemia, or familial LPL deficiency

  • accumulate chylomicron TAG in plasma
  • at higher risk for pancreatitis
21
Q

metabolism of VLDL (5 steps)

A
  1. made in liver, and secreted into blood with B-100
  2. get apo E and CII from HDL
    - some TAGs transferred from VLDL to HDL for cholesterol esters via CTEP (cholesterol ester exchange PRO)
  3. TAG degraded by LPL as in chylomicrons
  4. VLDL becomes IDL –> LDL in blood, with CII and E returned to HDLs
  5. LDL binds to specific receptor on surface of hepatocytes and extra-hepatic tissue
    - IDLs can also be taken up by hepatocytes thru receptor mediated endocytosis with apo E as ligand
22
Q

when does hepatic steatosis occur?

A

nonalcoholic fatty liver

-happens when imbalance between TAG synthesis and VLDL secretion

23
Q

what does CETP do? what does this explain if high TAG level?

A

cholesterol ester transfer PRO

  • catalyzes exchange of TAG from VLDL with cholesterol ester from HDL; CE on VLDL–>LDL are taken up by LDL receptor
  • relieves product inhibition of LCAT
  • the greater the concentration of TAG-containing particles in the blood, the greater the rate of exchanges
  • high TAG-containing LP particles correlate with greater cholesterol return to liver via VLDL and IDL particles
24
Q

how do LDL particles compare to other LPs?

A

have less TAG and more cholesterol and CEs

  • function to provide cholesterol to peripheral tissues, and return it to liver (LDL brings lipids to tissues)
  • binds LDL receptors that recognize B-100 and E receptors
25
Q

uptake and degradation of LDL (5 steps)

A
  1. LDL receptors are glycosylated transmembrane PRO clustered in clathrin-coated pits
  2. after binding, LDL-receptor complex is endocytosed
  3. coated vesicle loses clathrin coat, and fuses w/ other vesicles to form endosomes
  4. pH of endosome drops based on ATP-dependent H+ pumping into endosome
    - uncouples receptor from LDL particle
    - separates into distinct areas of CURL (compartment for uncoupling receptor and ligand)
  5. receptors recycled to plasma membrane, and endosome fuses with lysosome to degrade LDL, IDL, or chylos to release AA, FA, cholesterol, and PL
26
Q

what does deficiency of LDL receptor cause?

A

elevated plasma LDL cholesterol (type II hyperlipidemia, or familial hyperchoelsterolemia)

  • caused by increased protease (proprotein convertase subtilisin/kexin type 9) activity that degrades LDL receptor
  • also caused by defects in B-100
27
Q

what does high cholesterol do to liver LDL receptor?

A

diminishes expression to coordinate regulation of LDL receptor and rate limiting enzyme in cholesterol biosynthesis

28
Q

what happens if cholesterol is not needed immediately? how can this activity be increased?

A

if unnecessary for synthetic or structural purpose, it is esterified by acyl CoA: cholesterol acyl transferase (ACAT)

  • resulting cholesteryl ester is stored in cell
  • ACAT activity is increased by oversupply of intracellular cholesterol
29
Q

what is LDL receptor structure? what happens in each region?

A

encoded by gene created by exon shuffling

  • has 18 exons, and >45 kb in length, on short arm of Xm 19
  • has 6 regions:
  • -LDL binding region (40 residues, cysteine-rich domain; when acidic residues are protonated, Ca++ can’t bind, causing conformation change in domain 2)
  • -EGF-like and transducin beta subunit-like domain forming propeller-like moiety (where pH dependent conformational change occurs to cause LDL release)
  • -N-linked oligosaccharide domain
  • -O-linked oligosaccharide domain (N and O extend LDL binding domain away from bilayer, so more accessible to LDL particle)
  • -22 AA make single alpha-helix pass thru bilayer (TMD)
  • -cytosolic domain associates with clathrin-coated pit to initiate endocytosis when LDL bound (intracellular cytosolic domain)
30
Q

what are HDLs? functions?

A

heterogenous family of lipoproteins made in blood by addition of lipids to apo A1

  • circulating supplier of apo CII and E
  • nascend HDLs are discoid in shape, with PLs, apo A/C/E
  • take up cholesterol from peripheral tissues and other LPs (via LCAT to make CE and lysophosphatidyl choline), and return it to liver as cholesterol esters
  • involved in reverse cholesterol transport
31
Q

what does esterification of cholesterol maintain?

A

maintains cholesterol gradient to allow further uptake of cholesterol from peripheral tissues to HDL
-as HDL picks it up, CE converts from discoid to cholesterol-poor HDL3, then CE-rich HDL2 that carries CE to liver

32
Q

what is Tangier disease?

A

deficiency in ABCA1 that causes absence of HDL particles b/c of degradation of lipid-free apo A1

33
Q

what does hepatic lipase do?

A

degrades TAG and PL

-also participates in conversion of HDL2 to HDL3

34
Q

relationship between macrophages and scavengers

A

macrophages have high levels of scavenger receptor activity (SR-A)

  • bind range of ligands to cause endocytosis of modified LDL where lipid or apo B have undergone oxidative damage
  • scavenger receptor not regulated by intracellular cholesterol concentration
  • macrophages consume excess oxidized LDL to become foam cells, which participate in plaque formation
35
Q

how does plaque formation start?

A
  1. in response to endothelial injury from oxidized LDL, monocytes adhere to endothelial cells, move to intima, and convert to macrophages
  2. macrophages consume excess oxLDL to become foam cells
  3. foam cells accumulate, releasing growth factors and cytokines to stimulate migration of smooth muscle cells from media to intima; SMCs grow, make collagen, take up lipid, and may become foam cells
  4. low affinity, nonspecific, and nonregulated scavenger receptors take up oxLDL
  5. high affinity receptors specific for LDL are downregulated when the cell has enough cholesterol
36
Q

what causes oxidation of LDL? what inhibits it?

A

+ superoxide, nitric oxide, hydrogen peroxide, other oxidants
- vit E/C, beta-carotene, other antioxidants

37
Q

LDL receptor

  • what it recognizes
  • its function
  • deficiency?
A

recognizes apo B-100, E

  • expressed in most cells, and regulates entry of CE into cells
  • tight control mechanisms alter expression
  • involved in LDL uptake
  • deficiency causes familial hypercholesterolemia
38
Q

LDLR-related PRO (LRP)

  • what it recognizes
  • its function
A

recognizes apo E, but not apo B-100

-metabolism of apo E containing LPs (CM and VLDL remnants), but doesn’t recognize LDL

39
Q

PCSK9 (proprotein convertase subtilisin/Kexin 9)

  • what it recognizes
  • its function
A

modulates LDL receptor

  • upregulation causes degradation of LDLR and elevated LDL
  • downregulation is associated with lifelong decrease in LDL and lower CAD risk
40
Q

scavenger receptor A

  • what it recognizes
  • its function
A

recognizes oxidized LDL

  • macrophage uptake of oxLDL, but not regular LDL
  • not suppressed by high cellular cholesterol, so subintimal macrophages accumulate cholesterol to become foam cells and form fatty streaks
  • involved in early athersclerosis
41
Q

scavenger receptor B

  • what it recognizes
  • its function
A

recognizes HDL by liver and steroid producing cells

-includes CD36 and SR-B1

42
Q

how does atherosclerotic plaque buildup?

A

as plaque within blood vessel matures, a cap forms over expanding “roof” to partially occlude vascular lumen

  • vascular smooth muscle cells migrate from media to subintimal space, and secrete plaque matrix materials and metaloproteases that thin fibrous cap
  • thinning continues until cap ruptures, exposing contents to procoagulants in circulation, causing thrombus formation
  • if thrombus completely occludes blood vessel lumen, acute MI occurs
43
Q

what are the components of a standard fasting lipid panel?

A

total cholesterol: enzymatic (cholesterol esterase)
triglycerides: enzymatic (lipase)
HDL-C: direct after precipitation of apo-B
VLDL-C: estimated as TG/5
LDL-C: calculated by Friedewald formula
non-HDLC: TC - HDL-C

recommend fasting 12-14 hours to minimize postprandial hyperlipidemia

44
Q

what is Friedewald formula? when is it not valid?

A

total cholesterol = LDL + HDL + VLDL
LDL = TC - [HDL + VLDL] = TC - [HDL + TG/5]

not valid if TG > 400 mg/dL

45
Q

what is dyslipoproteinemia?

A

also dyslipidemia

  • constitutes major risk factor for athersclerosis and CAD
  • most common rarely cause symptoms or produce clinical signs present on exam, but need laboratory tests
46
Q

what are optimal lipid values?

A 
TC < 200
TG < 150
LDL < 100
HDL > 50 (female), > 40 (male)
non-HDL < 130
TC/HDL < 4 (reflects balance of transport of cholesterol to peripheral tissues with subsequent uptake in arterial walls, and reverse transport to liver)

Molecular and Cellular Princples of Medicine (42 decks)

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