Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Gastrointestinal System > Lipoproteins - Abali 2/19/16 > Flashcards

Lipoproteins - Abali 2/19/16 Flashcards

1
Q

total cholesterol calculation

Friedwald equation and application

A

LDL + HDL + VLDL

*where VLDL = triacylglycerol/5

LDL cholesterol = total chol - HDL chol - (total triglycerides/5)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

blood lipid levels (norms)

A

mg/dl

total lipid = 400-800

triacylglycerol = 40-160 (male), 35-135 (female)

total chol = 120-210

chol (free) = <160 - >240

phospholipids = 150-380

fatty acids = 8-14

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

cholesterol

  • definition
  • where synthesized
  • transport
A

27-C four-ringed, hydrophobic molecule synthesized by virtually all cells

  • esp liver, intestine, adrenal cortex, repro tissues
  • transported in plasma in lipoproteins
    • typically in esterified form (+ FA; not as free chol)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

cholesterol fx

A
  • structural component of membranes
    • abundant in myelin sheaths of CNS
  • precursor of
    • bile salts
    • 5 classes of steroid hormones (mineralocorticoids, glucocorticoids, androgens, estrogens, progestins)
    • vitamin D
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

cholesterol and link to cardiac pathologies

A

stem from regulation of amt of cholesterol in the serum and the propensity of LDL to accumulate in arterial walls (stroke, MI, etc)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

cholesterol structure

A
  • four fused hydrocarbon rings (“steroid nucleus” A-D)
  • 8C branched chain “tail” at C17 (D ring)
  • OH group at C3 (A ring)
  • double bond between C5=C6 (B ring)

​**reactive sites for esterification and redox rxns**

  • when esterified: FA attached to C3
    • more hydrophobic than free/unesterified chol
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

sources of liver cholesterol

A
  1. de novo synthesis in liver: VLDL (endogenous pathway of lipoprotein metab)
  2. diet cholesterol: chylomicrons from intestine (exogenous pathway of lipoprotein metab)
  3. synthesis in extrahepatic tissues (via HDL and LDL)

**each of the lipoproteins fx to transport cholesterol to/from peripheral tissues and liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

exit of cholesterol from liver

A

liver moves cholesterol out via…

  • secretion of VLDL
  • free cholesterol secretion in bile
  • conversion of chol into bile acids/salts

only mechanism body has to eliminate cholesterol:

excretion of bile acids (and derivative bile salts) in feces

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

cholesterol biosynthesis

  • location
  • C, cofactor, energy?, enzyme

know pathway [written]

A
  • takes place in almost all cell types in cytosol
  • major organs of de novo synth
    • liver
    • intestines
    • honorable mention: adrenal cortex, testes/ovaries, fetus
  • all C sourced from acetyl CoA
  • major cofactor: NADPH
  • ATP consumed
  • major step catalyzed by HMG-CoA reductase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

rate limiting step of chol synthesis

A

committed step catalyzed by HMG-CoA reductase

HMG CoA → mevalonic acid + free CoA

  • uses 2 NADPH
  • HMG-CoA reductase expression inhibited by cholesterol (feedback inhib)

(mevalonic acid → squalene, folds up → lanosterol → cholesterol)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

fates of mevalonic acid (besides cholesterol synthesis)

A

also makes terpenes/isoprenoids/isoprenes

  • farnesyl pyrophostphate, geranylgeranyl phyrophosphate: conjugated with proteins, serve as lipid anchors (ex. ras)
  • dolichol pyrophosphate: req for dolichol pathway of N-linked posttransl glycosylation
  • ubiquinones: reduced to ubiquinols like Coenzyme Q, donate e to etc in oxphos
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

fates of cholesterol

A
  • bile acids
  • steroid hormones
  • cholesterol esters
  • modified proteins like hedgehog
  • vitamin D
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

esterification of cholesterol

whats the point?

enzymes involved

A

esterification makes chol more hydrophobic : makes it easier to package, store, transport

  1. ACAT (liver) : acyl CoA cholesterol acyl transferase
  • free cholesterol (from diet/de novo synth)→ cholesteryl esters
    • hydrophobic, cant be incorp’d into membranes or transported through them
    • stored in lipid droplets in cytosol of hepatocytes and steroid-producing cells
  1. LCAT (bound to HDL in blood) : lecithin cholesterol acyl transferase
  • cholesterol → cholesteryl esters
    • uses FA from phospholipid lecithin (such as phosphatidyl choline) to esterify cholesterol in peripheral tissues
    • esters stored in HDL, taken to liver
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

regulatory effects of excess cholesterol

A

rising intracellular chol concentration…

  1. reduces action of HMG-CoA reductase on two fronts
  • stimulates proteolysis of existing HMG-CoA reductase
  • downregulates HMG-CoA reductase gene expression by downregulating RNA poly II activity
    • RNA poly II activity also stim by insulin (growth signal), inhib by glucagon (to save acetyl CoA for TCA cycle)
  1. activates ACAT
    * shuttles existing chol to esters for storage
  2. inhibits uptake of chol into liver cells

liver is the main clearinghouse!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

short term hormonal regulation of chol synthesis

(effect of insulin and glucagon)

A

HMGR (HMG CoA reductase) is the main target

  • has an active form (not P’d), and an inactive form (P’d)

conditions of low energy/low glucose

  • glucagon and epi (in effort to raise glucose levels and prevent it from being drawn off in acetyl CoA for chol synth) stimulate the inhibitor of PPI-1 (phosphoprotein phosphatase inhibitor-1)
    • _​_when active, PPI-1 inhibits phosphoprotein phosphatase (req for glycogen synth)
    • lower PPI-1 means more PP means more glycogen synth!
  • i.e. high [AMP], glucagon, sterols upregulate AMPK (AMP-activated protein kinase), which phosphorylates and deactivates HMGR

conditions of high energy/high glucose

  • insulin stimulates removate of phosphate via HMGR-phosphatase, which dephosphorylates inactive HMGR and makes it active

long term effects of intracell chol levels on HMGR transcription effected via tf SREBP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

long term hormonal regulation of chol synthesis

A

transcriptional regulation via SREBP2

(SREBP: sterol regulatory element binding protein)

  • SREBP2 is a cholesterol sensor in ER; main regulator of HMG-CoA reductase activity

low chol in ER

  • vesicles with SREBP2 move to Golgi → proteases cleave SREBP2 → N-term moves to nucleus and enhances transcription of genes (including HMG-CoA reductase, LDL receptors)

high chol in ER

  • no tf action of SREBP2 fragment
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

statins

(indication, mech of action)

A

(competitive) HMG-CoA reductase inhibitors

reduce risk of heart disease (CAD, MI)

ex. lovastatin

mechanism of action

  • HMG-CoA analogs, competitively bind to HMG-CoA reductase and block chol synth
  • lower levels of de novo synth in liver (and size of liver chol pool) trigger more efficient retrieval of LDL-cholesterol by liver
    • how? upregulation of LDL receptors (number and/or activity) on hepatocytes!
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

hepatic cholesterol homeostasis: summary

  • 4 regulatory mechs
A
  1. regulation of HMG-CoA reductase (HMGR) activity and levels
  • transcription (long term)
  • proteolytic degradation (high intracell chol)
  • hormonal reg (short term)
    • insulin (upreg)
    • glucagon (downreg)
  1. regulation of excess free intracell chol via ACAT
  2. regulation of plasma chol via…
  • LDL-mediated uptake
  • HDL-mediated reverse transport (periph tissues back to liver)
  1. inhibition of chol synth by drugs (statins: competitive inhibitors of HMGR)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

cholesterol dysregulation

A

LDL levels linked to incidence of coronary artery disease

  • high LDL linked to atherosclerosis
    • oxidized LDL : plaque : can rupture and resulting clot can block blood flow
  • overall…
    • narrowing of artery walls
    • lower blood/oxygen supply to heart
    • MI
    • death
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

xanthomas

A

cutaneous deposition of lipidosis

collection of cholesterol-laden foam cells deposited at…

  • hands and feet : tendon xanthomas : hypercholesterolemia + NO hypertriglyceridema
  • over joints : tuberous xanthomas : hypercholesterolemia + YES hypertriglyceridema
  • under skin (eyelid) : xanthelasmas
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

SLOS

A

Smith-Lemli-Opitz Syndrome

(chol deficiency due to mutation)

​metabolic disorder caused by mutation in DHCR7 (7-dehydrocholesterol reductase) on chromosome 11 (req for chol synth)

  • pt with SLOS unable to make sufficient chol for normal growth and devpt
  • facial features
    • ​microcephaly, ptosis (drooping eyelid), broad nasal bridge, upturned nose, micrognathia (undersized jaw), cleft palate
  • limb anomalies
    • ​short thumbs, polydactyly, syndactyly of second/third toes (most reported clinical finding)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

lipids in the blood

A

either FA associated with albumin or lipoprotein (lipid + protein)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

lipoprotein structure

A

surface

1. amphipathic lipids: phospholipids, unesterified cholesterol

2. proteins: lipoproteins

anhydrous core

1. triacylglycerols (aka TAG, TG)

2. cholesteryl esters (aka CE)

*during transport, each class of lipoproteins undergoes change in coposition*

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

apolipoproteins

  • definition (“apo”)
  • function
A

lipid-binding proteins in blood resp for transport of PL, C (surface); TAGs, CE (anhydrous core) between organs

  • “apo” = protein in lipid-free form

functions

  1. recognition sites or ligands for receptors
  2. structural components
  3. activators or coenzymes for enzymes involved in lipid metab
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

classification of lipoproteins

A

placed into general classes on basis of

  • electrophoretic mobility
  • density
  • tissue of origin
  • average composition of lipoprotein

broad particle classes: chylomicron, VLDL, LDL, HDL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

size/density of lipoproteins

A

chylomicrons

  • lowest density, largest size.
  • highest % lipid, lowest % protein.

progression moving down list: more dense, higher protein:lipid ratio

VLDL

LDL

HDL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

general phases of lipoprotein metabolism

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

classification of apolipoproteins

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

chylomicron (CM) snapshot

  • source
  • fx
  • major apolipoproteins
A
  • source: intestine
  • fx: transport of dietary TAG
  • major apolipoproteins: B48, CII, CIII, E
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

very low density lipoprotiens (VLDL) snapshot

  • source
  • fx
  • major apolipoproteins
A
  • source: liver
  • fx: transport of endogenously synth’d TAG
  • major apolipoproteins: B100, CII, CIII, E
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

low density lipoprotein (LDL) snapshot

  • source
  • fx
  • major apolipoproteins
A
  • source: formed in circ by partial brakdown of IDL
  • fx: delivers cholesterol to periph tissues
  • major apolipoproteins: B100
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

high density lipoprotein (HDL) snapshot

  • source
  • fx
  • major apolipoproteins
A
  • 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
33
Q

3 pathways for lipoprotein metabolism

A

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

34
Q

enzymes for TAG metabolism

A

TAG → FAs + glycerol

  1. lipoprotein lipase
  2. hepatic lipase
35
Q

3 key apoproteins found in “reservoir”

A

“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
36
Q

lipoprotein lipase

(basic fx and what happens to products)

A

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
37
Q

apo C-II

A

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)
38
Q

apo C-III

A

lipoprotein lipase inhibitor

39
Q

apo E

A

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
40
Q

lipoprotein lipase

(location, specifics of fx and products)

A

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
41
Q

hepatic lipase

  • source/location
  • fx
A

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)
42
Q

exogenous pathway

processing of dietary cholesterol

  • sources
  • stepwise processing & locations
A
  • 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
43
Q

how do fat soluble vitamins get into liver?

A

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

44
Q

fasting blood sample

  • what’s measured, what’s not (why?)
A

total TG = TG inside all lipoproteins (CM, CM remnants, VLDL, IDL, LDL, HDL)

fasting blood sample = VLDL, IDL, LDL, HDL

  • CM clearance t1/2 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
45
Q

endogenous pathway1

metabolism of VLDL

(FAs to VLDL remnants/IDL)

A
  • 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 (t1/2 = 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)
46
Q

endogenous pathway2

(VLDL remnants/IDL to LDL)

A

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
47
Q

endogenous pathway3

LDL delivery

A

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 t1/2 = days, so comprises most of what you see in a fasting sample
48
Q

endogenous pathway4

LDL clearance from blood

A
  • 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!

49
Q

endogenous pathway5

regulation of LDL receptors and chol intake

A

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
50
Q

endogenous pathway6

non-LDL-receptor-mediated LDL clearance

A

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

51
Q

endogenous pathway

summary

A
  • 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)

52
Q

apoB100 synth

A

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
53
Q

reverse cholesterol transport pathway

A

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)
54
Q

CETP

A

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

55
Q

HDL synthesis

A

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
56
Q

cholesterol synthesis in liver: regulation

A

regulated based on…

  • chol arriving through HDL
    • brought from periph cells, which add it to HDL
  • dietary chol returned by CM remnants
57
Q

CAD

A

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
58
Q

hyperlipidemia

A

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

59
Q

hypertriglyceridemia

  • criteria
  • prevalence
  • risks
  • risk factors
A

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
60
Q

familial hyperchylomicronemia

Type I

A

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)
61
Q

familial chylomicronemia

vs

primary mixed hyperlipidemia

A

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

62
Q

treating pancreatitis in familiar hyperchylomicronemia

A

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
63
Q

familial dysbetalipoproteinemia

Type III

A

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
64
Q

familial combined hyperbetalipoproteinemia

Type IIB

A

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
65
Q

treatment for hypertriglyceridemia

A
  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
66
Q

manifestations of primary hypercholesterolemia

A

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
67
Q

atherosclerotic plaque devpt

A
  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)

68
Q

role of Lp(a)

A

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
69
Q

familial hypercholesterolemia

(hyperbetalipoproteinemia)

Type II

homo vs heterozygous

A

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
70
Q

apoA1 deficiency

A

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
71
Q

LCAT deficiency

A

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)
72
Q

Tangier disease

familial alphalipoprotein dificiency

A

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

73
Q

mechanism of action of statins

(how do they lower plasma chol?)

A
  • 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
74
Q

ezetimibe

A

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
75
Q

bile acid binding resins

ex. cholestryamine

A
  • 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
76
Q

nicotinic acid (form of vit B3)

A

inhibits mobilization of FFA from periph adipose tissue to the liver

can lower plasma TG, raise plasma HDL, drop plasma LDL

77
Q

fibrate drugs

A

activate PPARalpha tfs → increased LPL activity

(+ apoAI, apoAII, - apoCIII inhibitor of lipolysis)

and

increased rate of FA beta-ox

78
Q
A

Gastrointestinal System (35 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions