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Cardio Week 3 > ICL 4.0: Lipoprotein Metabolism > Flashcards

ICL 4.0: Lipoprotein Metabolism Flashcards

1
Q

what are lipoproteins?

A

lipids are hydrophobic and have low solubility, need lipoprotein particles for transport in the blood for distribution to tissues

the major lipids are triglycerides and cholesterol

the amount and types of lipoprotein particles affects the risk for cardiovascular disease

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2
Q

what is the structure of lipoproteins?

A
  1. surface layer of amphipathic lipids = phospholipid and cholesterol
  2. core of nonpolar lipids = triacylglycerol and cholesterol ester
  3. apolipoproteins (peripheral and integral)

different types of lipoprotein particles contain specific proteins

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3
Q

what is the generalized function of apolipoproteins?

A
  1. part of structure of lipoprotein
  2. co-factors/activators for enzymes
  3. inhibitors for enzymes
  4. ligands for lipoprotein receptors
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4
Q

what are the major types of lipoproteins?

A
  1. chylomicrons
  2. very low density lipoproteins (VLDL)
  3. low density lipoproteins (LDL)
  4. high density lipoproteins (HDL)
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5
Q

what is the function of chylomicrons?

A

they are a type of lipoprotein that delivers dietary triacylglycerol from the intestine to adipose tissue
and, to a lesser extent, to liver and other tissues

they also deliver dietary cholesterol from intestine to liver

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6
Q

what is the function of VLDLs?

A

they are a type of lipoprotein that deliver hepatic triacylglycerol to adipose and other tissues

they are also the precursor of LDL!

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7
Q

what is the function of LDLs?

A

they are a type of lipoprotein that delivers cholesterol from liver to peripheral tissues

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8
Q

what is the function of HDLs?

A

they are a type of lipoprotein delivers cholesterol from peripheral tissues to liver

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9
Q

how are dietary triglycerides digested and transported?

A

triacylglycerides are digested into fatty acids and monoacylglycerols in the lumbar of the small intestines

then they’re transported into the cells and the triacylglycerides are re-synthesized in the cell

chylomicrons then transport the triacylglycerides to through the lymph system, to the blood, then finally to adipose cells –> they go through the lymph because they don’t want the fat to go to the liver

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10
Q

how are chylomicrons made?

A

intestinal endothelial cell absorb lipids from the lumen and packages them

RER makes apolipoprotein and then these proteins package the lipid components in the golgi and assemble the chylomicrons

they then get secreted into the lymph system which goes to the thoracic duct and gets delivered to the blood circulation

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11
Q

how are chylomicrons metabolized?

A
  1. intestinal mucosal cells secrete TAG-rich chylomicrons produced from dietary lipids
  2. apo C and apo E are transferred from HDL to the chylomicron
  3. in the circulation, extracellular lipoprotein lipase is activated by apo C which then degrades the TAG in the chylomicron into free fatty acids and glycerol –> free fatty acids go to tissues and glycerol goes to liver
  4. apo C is returned to HDL
  5. CE-rich chlymicron remnants bind through apoE to specific receptors on the liver and are endocytose
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12
Q

what is the importance of lipoprotein lipase?

A

normal fasting triglyceride levels is 100-150 mg/dL

if you have an LPL defieicency you have extremely high triglyceride levels because you can’t degrade them! there’s also a massive accumulation of chylomicrons because they’re just filled with TAGs that you can’t degrade

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13
Q

what is the main structural apolipoprotein in chylomicrons?

A

apoB48

apoCs

apoE

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14
Q

what is the main structural apolipoprotein in VLDLs?

A

apoB-100

apoCs

apoE

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15
Q

what is the main structural apolipoprotein in LDLs?

A

apoB-100

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16
Q

what is the main structural apolipoprotein in HDLs?

A

apoA-I

apoA-II

17
Q

how are VLDLs made?

A

VLDLs transport triglycerides and cholesterol from the liver to extra hepatic tissues –> this is because the liver doesn’t store a lot of TG or cholesterol

VLDL formation in the liver is dependent on apoB100 –> the lipoprotein is assembled in the RER and put into secretory vesicles which are secreted directly into the blood

a fatty liver is abnormal and is a sign of chronic alcohol abuse or diabetes

18
Q

what is the difference between chylomicrons and VLDLs?

A

CHYLOMICRONS
1. synthesized in intestine

  1. transport of dietary TG
  2. apolipoproteins = apoB48, apoA, apoC, apoE
  3. 90-1000 nm particle size

VLDLs
1. synthesized in liver

  1. transport of liver TG
  2. apolipoproteins = apoB100, apoC, apoE
  3. 30-90 nm particle size
19
Q

how are apoB100 and apoB48 synthesized?

A

they’re both derived from the same gene, the apoB gene

in both the liver and the tissue, you have the same primary mRNA transcript

in the intestine though, there is RNA editing where one of the bases is converted from a C to a U and that change creates a stop codon! so when the mRNA is translated, you get a truncated protein which is apoB48 which is used in chylomicrons –> because of this, the chylomicron can’t bind to the LDL receptor since it’s missing that domain

in the liver, the full mRNA transcript is translated so you get apoB100 which is used in VLDLs

20
Q

how are VLDLs and LDL metabolized?

A
  1. liver secretes TAG-rich VLDL particles containing primarily endogenously synthesized lipids
  2. apoC and apoE are transferred from HDL to the VLDL
  3. in the circulation, extracellular lipoprotein lipase is activated by apoC which then degrades the TAG in VLDLs into free fatty acids and glycerol –> the free fatty acids go to tissues and the glycerol goes to the liver
  4. apoC and apoE are returned to HDL –> loss of apoE and TAGs converts VLDL into LDL
  5. LDL binds to specific receptors on extraheptatic tissues and on the liver and are endocytose –> it primarily delivers cholesterol*
21
Q

what is the structure of HDL?

A

apoA and apoE on the outside

inside is made of triglycerides and cholesterol

22
Q

why is HDL cholesterol considered good cholesterol?

A

HDL transports cholesterol from the non hepatic tissues to the liver

it’s counteracts the function of LDL which takes cholesterol to tissues –> so it can transport cholesterol from plaques back to the liver

23
Q

how is HDL metabolized?

A
  1. lipid-poor particles like apoA-I and phospholipid originate from the liver and intestine
  2. plasma apoA-I acquires phospholipids and cholesterol from cell membranes, resulting in pre-B HDL
  3. continued uptake of cholesterol and its esterification transforms pre-B HDL to spherical HDL
  4. LCAT catalyzes esterification of cholesterol; cholesterol ester is returned to the liver by HDL which reverses cholesterol transport

HDL also transfers apoCs and ApoE to chylomicrons and CLDL in plasma –> apoCs and apoE are synthesized in the liver and bind to HDL in the plasma which are then transferred to VLDL and chylomicrons

24
Q

what is the cholesterol pathway?

A

acetyl CoA

acetoacetyl-CoA

HMG-CoA

Mevalonate

isopentenyl-PP

geranyl-PP

farnesyl-PP

squalene

cholesterol

25
Q

what step of the cholesterol pathway do statins act on?

A

HMG-CoA –> mevalonate via HMG-CoA reductase

statins inhibit HMG-CoA reductase

however, this step is early on in the pathway so it shuts down production of some useful downstream products which can cause side effects

26
Q

how do you regulate cholesterol levels?

A 
SREBP = SRE binding protein
SCAP = SREBP cleavage activating protein

low levels of cholesterol in ER activate SCAP which cleaves SREBP precursor

low levels of cholesterol result in the processing of SREBP which then translocates to the nucleus and activates transcription of genes = HMGCoA reductase and LDL receptors

HMGCoA reductase = increases cholesterol synthesis

LDL-R = increases uptake of cholesterol

27
Q

which drug classes lower LDL-C levels?

A

decreasing intracellular cholesterol stimulates LDL-R synthesis, increasing LDL clearance

  1. statins inhibit cholesterol synthesis
  2. bile acid sequestrants stimulate the elimination of cholesterol by conversion into bile salts
  3. ezetimibe inhibits cholesterol uptake in the intestine
  4. monoclonal antibodies to PCSK9 inhibit LDL-R degradation
28
Q

how does PCSK9 work?

A

PCSK9 binds to the LDL receptor and increases its proteolysis

this means that less LDL receptors will be recycled to the surface and then less LDL-C will be cleared

29
Q

how do lipoproteins play a role in atherosclerosis?

A

LDL gets trapped in intima of arterial walls and oxidized

oxidized LDL is then taken up by macrophages and plaque forms (foam cells)

HDL tries to reverse this by transporting cholesterol back to the liver

30
Q

how is dyslipidemia classified based on serum lipid levels?

A
  1. hypercholesterolemia = high LDL-C
  2. hypertriglyceridemia = high TG in VLDL
  3. low HDL
31
Q

what is dyslipidemia in metabolic syndrome?

A

low HDL-C

high TG

elevated small dense LDL

32
Q

what is the lipid hypothesis for CVD?

A

high LDL-C causes heart diseases

reducing the number of LDL particles is better than reducing cholesterol itself

33
Q

what is the genetic link to hypercholesterolemia?

A

Homozygous Familial hypercholesterolemia (FH) is associated with a 20-fold increase in the incidence of heart attacks in middle age

FH is due to a deficit in the LDL receptor, causing very high levels of LDL particles in blood

PCSK9 mutations reduce LDL levels and incidence of heart attacks

both conditions affect LDL particle numbers

34
Q

what is the Friedewald formula?

A

total cholesterol = LDL + HDL + VLDL

LDL = total - HDL - (triglycerides/5)

fast for 12-14 hours before and make sure TG <400 or else it’s not accurate

35
Q

what are normal LDL, HDL and total cholesterol levels?

A

LDL < 100

HDL 40-60

Total = <200

36
Q

which measurement from the lipid panel best predicts the risk of cardiovascular disease?

A

triglycerides:HDL ratio is the best predictor

low TG -high HDL is the a better prognosis and lower risk for CVD

high TG/HDL may not be causative but a marker for metabolic syndrome which can instigate CVD –> metabolic syndrome includes hyperglycemia, hyperinsulinemia, HTN, inflammation, low HDL, high TG

Cardio Week 3 (13 decks)

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