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CORE II Block 1 > Cholesterol pathways and transport > Flashcards

Cholesterol pathways and transport Flashcards

1
Q

What molecule is at the heart of cardiovascular disease?

A

cholesterol

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2
Q

Which lipid transport vehicle carries lipid soluble vitamins? What are these vitamins?

A

Chylomicron remnant carrier vitamins A, D, E, K

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3
Q

What event causes conversion of IDL to LDL?

A

When HDL in the blood takes off apo-E from IDL so that only apoB100 is left

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4
Q

What unique characteristic of HDL composition might be exploited in measuring its concentration directly?

A

HDL does not have apoB. An antibody recognizing apoB will pull down all the particles except for HDL.

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5
Q

In addition to dietary sources, how do humans meet their need for cholesterol?

A

Biosynthesis

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6
Q

What are the important functions of cholesterol?

A
  • forms vit D
  • backbone of bile acids and bile salts (solubilize exogenouse lipids). cyt p450 oxidizes one face of cholesterol, making amphipathic molecule. resulting micelle can transport lipids
  • steroid hormone synthesis using cyt p450 enzymes
  • membrane component (regulates fluidity, forms lipid rafts)
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7
Q

What do glucocorticoids do?

A

Fight or flight response. They upregulate genes of gluconeogenesis to provide energy to get out of a situation. Also turns on responses to inflammatory system.

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8
Q

Androgens and estrogens?

A

Hormones that determine sexual development

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9
Q

Describe gel electrophoresis of lipoproteins from the origin.

A

chylomicron (doesnt move much), LDL, VLDL (very negative, travels far), HDL (smallest, travels far)

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10
Q

Describe appearance of plasma after a fatty meal.

A

It is milky due to high content of chylomicrons.

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11
Q

What might be responsible for a buildup of chylomicrons in the plasma even when fasting?

A

LPL or apoCII problems

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12
Q

What would cause a buildup of IDL particles?

A

ApoE is defected, becauase it is responsible for bringing IDL particles into the liver and out of the plasma.

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13
Q

What causes a buildup of LDL in plamss?

A

-LDL receptor muttion on liver

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14
Q

What is the effect of statins on cholesterol?

A

They inhibit HMG coA reductase, reducing sterol levels in the cell. This induces transcription of the SREBP so there are more LDL receptors on surface of cell. This makes serum cholesterol decrease.

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15
Q

Give an overview of the LDL receptor pathway

A
  • LDL binds receptor on cell surface
  • clathrin-coated pit forms around entire comlpex
  • endosome picks up ATPase (proton pump) to decrease pH in the endosome, causing receptor to dissociate and be recycled (PCSK9 can balance recycling by binding and degrading receptors. If we block PCSK, we get greater numbers of LDL receptors on the cell and a greater ability to clear serum cholesterol.
  • endosome becomoes lysosome and everything is degraded, releasing free cholesterol and fats
  • acyl cholesterol acyltransferase (ACAT) esterifies cholesterol so it can be stored
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16
Q

What is reversed cholesterol transport?

A

HDL picks up cholesterol from a cell type. Cholesterol is esterified and lipid contents are balanced among LDL and VLDLs. Mature HDL can finally deliver cholesterol to liver where bile salts may be made.

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17
Q

Are myocardial infarction and lactic acidosis related?

A

Yes, O2 intake decreases, so ETC stops and NADH accumulates. Accumulation of NADH slows the TCA cycle (inhibits isocitrate dehydrogenase) so the only way to regenerate NAD for ATP synthesis via glycolysis is lactic acid fermentation.

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18
Q

When there is a buildup of ATP and citrate (TCA cycle is slowed) as a result from a highly nutritious meal, how can the energy be stored?

A

Can be exploited into the cytosol to make cholesterol and fatty acids CItrate is broken down into acetyl-coA and OAA. OAA is converted to malate which is converted to pyruvate, generating NADPH as a secondary source of NADPH to fuel fatty acid synthesis.

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19
Q

Why does citrate build up when NADH and ATP is high?

A

NADH inhibits isocitrate dehydrogenase, so the TCA cycle cannot progress forward as quickly, causing citrate to buildup.

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20
Q

Why are cholesterol molecules esterified to fatty acids under high energy?

A

Because free cholesterol is hard to store. Esterification makes it more hydrophobic so storage is more efficient.

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21
Q

Why is storage of acetyl coA as FA highly efficient?

A

The oxidation of each acetyl coA molecule from FA forms large amound of NADH and FADH2.

22
Q

Why is cholesterol only made under high energy conditions?

A

Because cholesterol synthesis is highly expensive, requiring many enzymes, ATP, and NADPH.

23
Q

In the synthesis of cholesterol what are isoprene units and how are they made?

A

They are 5-carbon units made from acetyl coA.

24
Q

How does ketogenesis regenerate NAD when NADH is abundant?

A

It is used to reduce acetoacetate to form beta hydroxybuterate, the predominant ketone body.

25
Q

What is the reaction catalyzed by HMG coA synthase in the formation of ketone bodies and in cholesterol synthesis?

A

Once two acetyl coA molecules have been condensed to make acetoacetatyl coA, HMG coA synthase catalyzes the condensation of a third acetyl coA, forming HMG coA.

26
Q

What are the sources of NADPH for cholesterol synthesis?

A

citrate-malate-pyruvate shuttle which is needed to get acetyl coA into the cytoplasm generates NADPH in the cytoplasm from the oxidation of malate to pyruvate.

27
Q

In the citrate-pyruvate shuttle, what molecules can pass through the mito membrane?

A

pyruvate can enter the mito, and citrate can leave it to enter the cytosol. This is why this shuttle is used to move acetyl-coA into the cytosol, because it can be condensed with OAA to form citrate.

28
Q

Describe the rate-limiting step of cholesterol synthesis.

A

After condensation of 3 acetyl coA molecules to generate HMG coA, HMG coA reductase uses electrons from NADPH to reduce HMG coA to mevalonate.

29
Q

How is HMG coA reductase regulated?

A
  • statins act as a competitive inhibitor to HMG coA reductase (main way to combat serum cholesterol pharmacologically)
  • inhibited by phosphorylation (glucagon = low energy = phosphorylation)
  • HMG coA reductase is an ER transmembrane protein with a sterol sensing domain facing the lumen. Binding of sterols here attracts the insig protein which marks HMG coA reductase with ubiquitin for degradation.
  • SREBP activation and transcriptional regulation
30
Q

What are the two classes of statins?

A

Natural and synthetic

31
Q

Describe transcriptional regulation of HMG coA reductase

A

under low levels of cholesterol, SREBP is activated and activates SCAP so it no longer interacts with INSIG. This causes a vesicle containing SCAP to bud off from the ER towards the golgi, and SREBP is released from the complex so that its nuclear localization signal is revealed. SREBP is cleaved off by site 1 and 2 proteases which are added at the golgi. SREBP then upregulates transcription of HMG coA reductase and LDL receptors.

32
Q

After mevalonate is formed using HMG coA reductase, what is the resulting building block of cholesterol which is formed? What energy molecule is highly involved in its synthesis?

A

isoprene (isopentenyl diphosphate) resulting from several phosphorylations of mevalnate. ATP is a large energy source for this, provide leaving groups for condensation of isoprene units.

33
Q

Describe the formation of lenosterol from isoprene building blocks.

A
  • isoprene units condensed head to tail to form 15 carbon-member farnesyl pyrophosphate
  • two farnesyl pyrophosphate units come together in head-to-head condensation to form squalene.
  • lanosterol synthase closes squalene into rings, forming lenosterol. This molecule is essentially a finished cholesterol molecule.
34
Q

What are the roles of farnesyl pyrophosphate other than in cholesterol synthesis?

A
  • prenylation of proteins on their C-termini for anchoring in the membrane (ex: RAS)
  • synthesis of dolichol for anchoring glycosylation sugars in the ER membrane
  • vitamin D3
  • ubiquinone
35
Q

Where are chylomicrons synthesized?

A

In the enterocytes of the intestine

36
Q

Where is VLDLs made?

A

In the liver. Hence, the large amount of TAGs.

37
Q

Describe the fate of dietary lipids

A
  1. bile emulsifies fats and attracts pancreatic lipase
  2. TAGs are broken down by pancreatic lipase and taken into enterocytes
  3. TAGs are assembled around apoB48 (with the help of enzyme MTP) and packaged into chylomicrons
  4. chylomicrons are secreted into the blood where they pick up apoC and apoE from HDLs
  5. fatty acids are dropped off at adipose and muscle via capillaries after breakdown from TAG by lipoprotein lipase (LPL activated by apocII, and inhibited by apocIII to ensure balance)
  6. shrunken chylomicron remnant, which now has apoE exposed (was on the inside), binds by apoE to the chylomicron remnant receptor on the liver so that insoluble vitamins and cholesterol can be delivered to the liver.
38
Q

At what point is a chylomicron called a chylomicron remnant?

A

when apoE is exposed on the surface and can bind to receptors on liver cells

39
Q

Loss of apoCIII would do what to TAG levels?

A

It would result in lower TAG levels, because lipoprotein lipase would never be inhibited.

40
Q

Describe the fate of endogenous lipids and their transport.

A
  1. in the liver, TAGs assemble around apoB100 with the help of MTP enzyme, forming imature VLDL
  2. In blood, imature VLDL picks up apoE, apoCII, apoCIII from HDL, becoming mature VLDL
  3. apoCII-activated LPL allows for delivery of fatty acids and glycerol to adipose and muscle.
  4. shrinking of VLDL exposes apoE, making it an IDL or VLDL remnant. IDL is delivered to liver by binding of apoE to IDL receptor.
  5. IDLs that aren’t taken up by the liver can bump into HDL, losing apoE, and becoming an LDL. The LDL only has apoB100.
41
Q

Under what energy state will VLDLs be made?

A

High energy, as they transport endogenous (house-made) lipids

42
Q

Describe the LDL receptor pathway.

A
43
Q

HDL is a cholesterol scavenger, or a reverse cholesterol transporter. What does this mean?

A

HDL is assembled in the plasma mostly from components obtained from degradation of other lipoproteins. It can be thought of as a janitor cleaning up the plasma.

44
Q

What effect do statins have on LDL receptors?

A

They increase the txn of LDL receptors indirectly by inhibiting cholesterol synthesis (cell must take more in)

45
Q

What is the clinical importance of PCSK9?

A

Normally, PCSK9 degrades LDL receptors. Development of PCSK9 inhibitors has decreased levels of serum cholesterol in patients.

46
Q

How do HDLs scavenge lipids from cells?

A

HDLs use an ABC transporter to move components which opens and closes with ATP hydrolysis. ABCA1 specifically loads cholesterol and phospholipids into nascent HDL particles.

47
Q

Describe maturation of pre-beta HDL particles.

A

Once free cholesterol is taken up, the HDL is called a pre-beta HDL. ApoA1 helps to hold free cholesterol in the pre-beta HDL. Once the free cholesterol is esterified to fatty acid by LCAT, the HDL is matured and forms a sphere, as the cholesterol can pack more densely.

48
Q

What two enzymes are required for HDL maturation?

A

LCAT and CEPT. CEPT helps balance the load of cholesterol esters and TAGs among the different lipoproteins

49
Q

What do LCAT and ACAT have in common?

A

They both esterify groups to cholesterol. ACAT is in the cell, and LCAT is extracellular.

50
Q

To what receptor do HDLs bind?

A

The scavenger receptor (SR) on the liver.

51
Q

Where does the liver get its cholesterol for bile synthesis?

A

Mostly delivered by HDLs.

CORE II Block 1 (5 decks)

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