Lipids 3: Lipoproteins

Question 1

How are the structures of micelles and lipoproteins similar and different?

Answer 1

Similar
* both have a hydrophobic core and hydrophilic head forming a spherical droplet
* both have TGs and CEs held within
Different
* The outer layer of the micelle is surrounding by bile acids
* the lipoprotien membrane is made up of phospholipids and has embedded proteins

Question 2

Where do chylomicrons first go after leaving the enterocyte cells?

Answer 2

The chylomicrons go into the lymph first where then enter into the peripheral circulation to go to the heart and adipose before going to the liver.

Question 3

What is the purpose of the apoproteins on lipoproteins?

Answer 3

The apoproteins serve as a signal for cells to recognize the lipoprotein.
* the apoproteins are made in the enterocyte and packaged with the lipoproteins

Question 4

How are lipoproteins classified?

Answer 4

Classified by density such that the more lipids they have the lower the density.
* chylomicrons (least dense)
* VLDL
* IDL
* LDL
* HDL (most dense)

Question 5

For chylomicrons what is:
* site of synthesis
* major function
* major apolipoproteins
* residence time in plasma

Answer 5

• site of synthesis: intestine
• major function: transport dietary lipid to circulation
• major apolipoproteins: B48 (also CI, CII, CIII, E)
• residence time in plasma: 5-15 min

Question 6

For chylomicron remnants what is:
* site of synthesis
* major function
* major apolipoproteins
* residence time in plasma

Answer 6

• site of synthesis: conversion by LPL from chylomicrons
• major function: transport dietary lipids to liver
• major apolipoproteins: B48 and E
• residence time in plasma: 15-30 min

Question 7

For VLDL what is:
* site of synthesis
* major function
* major apolipoproteins
* residence time in plasma

Answer 7

• site of synthesis: liver
• major function: transport endogenous cholesterol and TG
• major apolipoproteins: B100 (also E, CI, CII, CIII)
• residence time in plasma: 15-30 min

Question 8

For IDL what is:
* site of synthesis
* major function
* major apolipoproteins
* residence time in plasma

Answer 8

• site of synthesis: conversion from VLDL by LPL
• major function: intermediate for LDL
• major apolipoproteins: B100 (also E)
• residence time in plasma: transient

Question 9

For LDL what is:
* site of synthesis
* major function
* major apolipoproteins
* residence time in plasma

Answer 9

• site of synthesis: conversion from IDL by HL
• major function: deliver cholesterol to tissues
• major apolipoproteins: B100
• residence time in plasma: hours

Question 10

For HDL what is:
* site of synthesis
* major function
* major apolipoproteins
* residence time in plasma

Answer 10

• site of synthesis: liver and intestine
• major function: transport cholesterol to liver
• major apolipoproteins: AI (also AII, CI, CIII)
• residence time in plasma: hours

Question 11

What are the 2 main tissues with census got lipoproteins?

Answer 11

liver and SI

Question 12

VLDL/LDL metabolism in the fasting condition

Answer 12

Lipoproteins (B100) are being secreted
* Liver secretes VLDL into circulation and lipoprotein lipase breaks it down into FFAs and glycerol to be used for energy by the muscle.
* The VLDL gets smaller to become IDL which then has hepatic lipase break it down more to LDL
* LDL pretty much just has cholesterol left and goes back to liver to be removed by LDLr

Question 13

HDL in the fasting/fed condition

Answer 13

Liver also synthesizes HDL (A1)
* Goes to the periphery and takes cholesterol away from the peripheral cells, so removes it before it builds up too much at those sites and brings back to liver to get rid of it.
* Not really controlled by fed and fasting state but is important for overall cholesterol homeostasis

Question 14

Chylomicrons in the fed state

Answer 14

Start eating a meal and have lipids in meal which are digested and packaged in SI with B48 and releases as Chylomicrons which get secreted in lymph and goes to periphery. Can see Chylomicrons with lots of TG and goes to adipose tissue where lipoprotein lipase removes TG and glycerol from here and get taken up by adipose to be stored.
* In fed state lots of calories coming in and dont need that TG for energy so stored until we need it which is typically during fasting.
* Chylomicron remnants left with B48 and some lipids left and this goes to the liver.

Question 15

What are Apolipoproteins?

Answer 15

Main protein content of lipoproteins
* KNOW: B48, B100, ApoA1

Question 16

Functions of apolipoproteins?

Answer 16

• facilitation of lipid transport to receptors
• binding of to cell surface receptors, can act as ligands for other interactions in vessel wall
• activation of enzymes in lipid metabolism

Question 17

How do apoliproteins effect the enzyme LPL?

Answer 17

ApoCII activates and ApoCIII inactivates

Question 18

What is the role of of the enzymes LPL, HTGL, LCAT?

Answer 18

• Lipoprotein lipase: hydrolizes TG in chylomicrons and VLDL
• hepatic triglyceride lipase: Processes apoE containing lipoproteins such as hydrolyzing TG in HDL and IDL
• lecithin cholesterol acyltransferase (LCAT): ApoA1 is cofactor so catalyzes the esterification of HDL cholesterol in cholesteryl esters)

Question 19

Cholesterol fractions in plasma during fasting

Answer 19

Mostly LDL and HDL

Question 20

What does the ratio of LDL:HDL indicate?

Answer 20

indicates relative risk of CVD

Question 21

What is the receptor mediated clearance of lipoproteins?

Answer 21

Removal of LDL via cell receptors
* Liver is the main way → ~90% of lipoproteins are remvoed from plasma by heaptic LDLr
* LDLr is present on many cell types, predominantly hepatocytes, but all cells need cholesterol for membrane synthesis.

Question 22

What do LDLr regulate?

Answer 22

Levels of LDLr regulate LDL (ligand apo B100) and chylomicron remnant (ligand apo E) removal from plasma.
* This can be manipulated

Question 23

Describe how to LDLr works?

Answer 23

Receptor-mediated endocytosis for cholesterol homeostasis
* LDLr in plasma membrane so LDL with Apo B48 binds and when it binds, the receptor creates coating and makes vesicle and the whole vesicle gets transported into the cell and the lipo gets taken to a lysosome which breaks down everything but releases the cholesterol which goes to different parts of the cell but mostly the ER and cell gets the supplied cholesterol.

Question 24

Where does cholesterol synthesis occur?

Answer 24

Takes place in the cytosol close to the ER

Question 25

How does the body get cholesterol?

Answer 25

Either from lipoproteins or can synthesize it. So when cell needs cholesterol it will take some from plasma via the lipoproteins and will also increase synthesis.
* Synthesis is a long process starting off with AcetylCoA and takes a lot of energy to make.

Question 26

What is the RLS of cholesterol synthesis?

Answer 26

HMG-CoA reductase
* HMG-CoA reductase regulated cholesterol very closely to the amount we need. When you have enough cholesterol in cell it will turn off synthesis and reduce the amount coming in from the blood (reducing amount of LDLr on membrane).

Question 27

What controls HMG-CoA reductase?

Answer 27

HMG CoA reductase is under negative feedback control by mevalonate and cholesterol, which are both products

Question 28

What drugs inhibit HMG-CoA reductase and why is this important?

Answer 28

Statin class of drugs
* Inhibit the HMG-CoA step. Therefore to get cholesterol in cell when needed then need to upregulate the plasma uptake so increases expression of LDLr so more binding partners and end up reducing the amount of LDL plasma.

Question 29

cellular cholesterol regulation with:
* excess cholesterol
* low cholesterol
* statin therapy

KNOW THIS

Answer 29

• excess cholesterol: Reduce cholesterol synthesis & lower LDL receptor
• low cholesterol: Increase cholesterol synthesis & increase LDL receptor
• statin therapy: Reduce cholesterol synthesis & increase LDL receptor

Question 30

How much of cholesterol metabolism is endogenous?

Answer 30

de novo synthesis 800-1500mg/day
* Hepatic synthesis: 50%, secreted VLDL
* Intestinal synthesis: 30%, secreted chylomicrons

Question 31

How much of cholesterol metabolism is exogenous?

Answer 31

Animal products in diet 100-300mg/day (dietary intake)
* Diet contributes little to total amount of cholesterol, we essentially make what we need?

Question 32

How might cholesterol metabolism differ between a meat eater and a vegan?

POTENTIAL QUESTION

Answer 32

meat eater might just synthesize less and vegan is unlikely to be in deficit since we synthesize most of it anyways
* If you consume excess choelsterol in normal situation, such as meat eater, most normal people will just synthesize less, so decreased HMG-CoA reductase, so you essentially end up at the exact same spot.

Question 33

What factors can impact cholesterol metabolism homeostasis?

KNOW THIS

Answer 33

Hypercholeresterolemia
* increased blood cholesterol (LDL or chylomicrons) which is associated with increased dietary total fat; cholesterol with SFAs increasing risk of developing atherosclerosis
* Can also be genetic disorder

Question 34

What are common risks/causes for dyslipidaemia?

Answer 34

can lead to CVD
* genetic
* dietary
* lifestyle

Question 35

HDL metabolism

Answer 35

Reverse cholesterol transport
* Secreted from the liver and goes to the periphery and takes cholesteryl ester out of the periphery bringing it back to the liver to be secreted into bile as cholesterol or bile acids.
* Body cannot break down cholesterol so must be excreted in this way

Question 36

What happens to the cholesterol once it is secreted into bile?

Answer 36

HDL is taking cholesterol from the periphery (aorta for example) and bringing it to the liver which converts it to bile acids or directly as choelsterol into bile which then goes to the SI and helps to absorb TG and lipids from the diet but absorption back into circulation is not efficient and it is typically excreted into the feces

Question 37

Summary of lipoprotein metabolism

Answer 37

• Cholesterol can go back to liver to be removed or high concentrations can go into vessel and start accumulating cholesterol so build of the Chylomicrons remnants or VLDL (early stages of CVD)
• HDL is much smaller and can go into plaques and remove cholesterol from the plaques and take it away back to the liver.