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MCD > Lipid Transport > Flashcards

Lipid Transport Flashcards

1
Q

Lipid transport
3 pathways
what are they called? and where do they go from and to where?

A

Lipids are transported by three interlinked systems

The exogenous pathway transports lipid from the gut to the liver

The endogenous pathway transports lipids synthesised by the liver to non-hepatic tissue including adipocytes

Third pathway takes lipid from the circulation and from non-hepatic tissue back to the liver

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2
Q

Fats and Lipids in Circulation include

what fats are transported in blood? (4) %?

solubility in water? hence how are the transported and why? (2)

fatty acids, polyunsauturated FA key function? give example of this (insulin)

what is UCP-2 and 3?

A
  • Triacylglycerol (triglycerides) (45%)
  • Cholesterol esters and free cholesterol (15%)
  • Phospholipids (35%)
  • Free fatty acids (5%)

The %’s given in human plasma vary greatly with nutritional state.

All are insoluble in water, they are not transported completely freely dissolved in the blood.
This is because they are hydrophobic and also, they interfere with membrane structure.

Fatty acids particularly polyunsaturated FA are ligands for transcription factors involved in energy metabolism. For example they play a role in the regulation of insulin metabolism. They up regulate lipid oxidation in the liver and muscle and down regulate genes involved in lipogenesis in the liver and adipose tissue. Also increase expression of UCP-2 and 3 in mitochondria to increase thermogenesis

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3
Q

Free Fatty Acids

what 2 ways are lipids transported?

when does saturation occur?
what are they formed from and where are they stored?
how do they enter cells and intracellular conc of FFA?

A

Most lipids are transported in lipoproteins, but there is some transport of free fatty acids. These are transported not exactly free but instead bound to albumin.

  • Saturation occurs at about 2mM FA molecules
  • These are formed from triacylglycerides and stored in adipose tissue.
  • Fatty acids enter cells by simple diffusion and intracellular concentration of FFA is kept low. (converted into other molcecules)
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4
Q

Lipoproteins

describe the structure

how many types of lipoproteins and what are they classifed by?
what are they?

A

Most lipids are transported in the blood as plasma lipoproteins, these are relatively large structures consisting of both the lipid and large proteins (called apolipoproteins). There are five types of lipoproteins, classified by their density:

o	Chylomicrons 
o	Very low-density lipoproteins (VLDL)
o	Intermediate density lipoproteins (IDL)
o	Low density lipoproteins (LDL)
o	High density lipoproteins (HDL)

Chylomicrons have the least density (and largest), while HDLs have the highest. Each particle has a different function.

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5
Q

Lipoprotein - structure

describe structure
what is in the hydrophobic core
what distinguishes lipoproteins (2)

A

As can be seen the lipoprotein consists of a large protein with phospholipids orientated similarly to how they are in a membrane, but instead as a single layer.

Then in the hydrophobic core is the hydrophobic compounds like cholesterol esters and triglycerides.

  • The thing that distinguishes lipoproteins is the apolipoprotein present and the amount of triacylglycerol/lipid that is present. The amounts in a single particle do vary however depending on where in the circulation the lipoprotein is.
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6
Q

Lipoprotein composition

composition of chylomicrons?
composition of HDLs?

A

Chylomicrons have a very low density, they have high TG and low protein. HDLs have a very high density with low TG and high protein.

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7
Q

Protein composition of Lipoprotein

apoproteins present in the 5 lipoproteins?

how does this help distinguish?

A

Lipoprotein Apolipoproteins/Apoproteins

Chylomicrons B48, Apo CII, and E
VLDL B100 Apo CI, CII, CIII and E
IDL B100, Apo E
LDL B100
HDL Apo AI, AII, CII, CIII, D, E

Because of the unique apoproteins present, it can be used to determine which one it is and where it was synthesised e.g. apoprotein B48 in chylomicrons.

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8
Q

Apolipoproteins or Apoproteins
These apolipoproteins have multiple functions

structural?
lipid solubilty?
enzyme? (2 examples?
tissue targetting? (2 examples)

A

o Structural
Form a substrate in which lipid can be constructed

o To solubilise lipids
Allowing body to transport a difficult class of molecules

o They can act as enzymes or enzyme cofactors (co-enzymes)
Apo C2 which is important for activating lipoprotein lipase
Apo A1 is important for Lecithin which is crucial for
cholesterol acyltransferase

o They allow tissue targeting to specific tissues,
Apo B100 and Apo E bind to the IDL receptor,
Apo E binds to the HDL receptor

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9
Q

Dietary Lipids

what happens to the triglycerides we eat? what are they broken down by and into what?

what happens to these? how do they form chylomicron and with what?

where are chylomicrons released? where do they go? what is the significance of this?
how is this different to digested proteins ad carbs?

density?
what is added in the SER?
how is it secreted/released?
what 3 things are transferred by HDLs?

A

Triglycerides we consume are broken down by lipases in the gut to fatty acids and monoacylglycerols.

  1. These pass from the gut lumen into the gut epithelial cells and converted back into triglycerides.
  2. The triglycerides are then assembled into a chylomicron along with other lipids (phospholipids and cholesterol) and proteins.
  3. Chylomicrons are then released into the lymphatics which carries them via the thoracic duct to the SVC.
  4. By this pathway dietary fats avoid the direct delivery to the liver and instead made available to extrahepatic tissue (i.e. they have first call).

This is very different to digested proteins and carbs which are released into the portal vein and delivered directly to the liver.

ALSOOOO,
Low density due to high TG

B48 added in the SER

Secreted by reverse pinocytosis in to the lymphatics

Apo C2, C3 and E transferred from HDLs

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10
Q

Removal of Fatty Acids

what is expressed on top of endothelial cells? what activates this?

Km of this in adipocytes vs muslce? meaning?

what happens when it is activated? what happens to density when this happen?

A

Lipoprotein lipase (LPL) is expressed on top of endothelial cells, this LPL is activated by an apolipoprotein on the lipoprotein, this is Apo C2.

(Km of LPL isoform in adipocytes greater than muscle hence muscle take up FA in preference to adipocytes)

When LPL is activated the TG is broken down and there is diffusion across the membrane of free fatty acid across the membrane.

This continues as the chylomicron goes around the circulation, as it does this is gains density.

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11
Q

There are a number of disorders of lipid transport which can lead to disease states, examples are the hyperlipidaemia which result in high levels of circulating lipids

name 3 examples of diseases and what causes them

A
  • Type 1 = Deficiency in lipoprotein lipase or Apo C2, characterised by high plasma triglyceride
  • Type 2 = Characterised by high LDL, most caused by genetic defect in synthesis processing or function of LDL receptor
  • Type 4 = Most common form results in raised VLDL concentrations often due to obesity or alcohol abuse
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12
Q

Chylomicrons

what is the content a reflection of?
density and why?
vitamins? (2)
half life? half life of TG? hence what happens?

what happens to density as it goes around? why?
new name? removed by? how?

A
  • The content of a chylomicron reflects the meal composition.
  • They are low density due to TG.

• Chylomicrons also contain fat-soluble vitamins
o Vitamins A and E.

• They circulate for about 1hr, but the half-life of TAG is only 5min.
So, they are rapidly modified by lipoprotein lipases in the circulation which breaks down the TG causing uptake of fatty acids by tissue.

• As they go around the circulation, the density of these particles increases (as TG removed), these are called chylomicron remnants and are removed by the liver
o They do this by interaction of Apo E with receptors on hepatocytes.

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13
Q

VLDLs

what is primary function?
synthesised where?
what apolipoprotein are they released with and what do they acquire?

what do VLDLs also interact with?
half life of TG? hence?

A

So earlier we spoke of chylomicrons which are solely important for transporting exogenous lipids from gut around the circulation, ultimately whatever is left ending up in the liver.
• The primary function of VLDLs is to transport lipids derived from the liver around the body.

• VLDLs are synthesised in the liver, in the ER and Golgi body. They are released with apolipoprotein B100 (as a nascent particle) and they acquire Apo E and C2.

VLDLs also interact with endothelial layer and are metabolised by LPL, the TG associated with the lipoprotein also has a longer half-life, of 15-60min.
• Lipids associated with VLDLs are on a greater distance transport system.

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14
Q

VLDL formation enhanced

4 things?

A

VLDLs formation is enhanced by:

  • Dietary carbohydrate
    o When we have excess, excess is synthesised into lipids, usually VLDLs
  • The amount of circulating FFA
  • Alcohol
    o Enhances VLDL synthesis hence increasing lipid transport
  • Raised insulin and decreased glucagon
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15
Q

LDL

what are they a major carrier of?
half life?
metabolism?
what do they regulate? through what?

A
  • LDLs are the major carrier of cholesterol and have a long half-life.
  • They are metabolised slowly – 3 days. (therefore can be metabolised)
  • They carry cholesterol to the periphery and regulate de novo synthesis, through Apo B100 acting on receptors on hepatocytes.
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16
Q

HDL

what do they take up? from? and to where? (2)

where are HDLs made?
what are they a circulating reservoir of? where are these also obtained from? (2)
what do they remove? where from? what else can they remove and from where?
what enzyme do they have and what does this do?
how does HDL bind?
where can it return the molecule it takes up? who can it also ransfer it to? (2) how?

what is the most important function? where is it particularly important and why?

A

HDLs reverse cholesterol transport, they take up cholesterol from the circulation (from VLDLs etc.) or dead and dying cells (mopping up) and take the cholesterol back to the liver and steroid producing cells.

o HDLs are made in the liver and intestine.
o They are a circulating reservoir of apolipoproteins (C2 and Apo E).
o Apolipoproteins are also obtained from VLDLs and chylomicrons
o They remove cholesterol from the plasma. Nascent HDL acquire cholesterol and phospholipids from endothelial cells
o They contain the enzyme lecthin cholesterol acetyltransferase (LCAT) which esterifies cholesterol hence preventing it from returning to the cell.
o HDL binds to lipoproteins and cells via Apo E, which is important for cholesterol transfer.
o Cholesterol rich HDL can return cholesterol to the liver but also transfer it to VLDLs and LDLs – cholesterol ester transfer protein

Most important function reverse cholesterol
transport - This transfer does not require enzymes

Particularly important in vascular cells – prevents
foam cell formation

17
Q

ways HDL is formed (3)

A

Can be created in 3 ways

  1. As nascent particles by the liver and intestine
  2. Budding of apolipoproteins from chylomicrons
  3. From free ApoAI
18
Q

HDL/LDL

what is the correct ratio?

A
  • LDL/HDL are commonly put into the categories of HDL as good cholesterol and LDL as bad cholesterol. This is not a great way of looking at it ultimately as cholesterol is cholesterol. We need the correct balance of both.
  • Normal individuals have a ratio of 3.5
19
Q

Lipoproteins are removed from the circulation by receptor mediated endocytosis

receptor?
affinity?
lipo protein binds to?
binds to what?
regulated by?
tissue distribution?
A

Receptor
LDL LDL - like

Affinity
High High

Lipoprotein
VLDL and LDL VLDL, HDL, chylomicron

Binds to
ApoB100, ApoE ApoE

Regulated by
Cholesterol cholesterol

Tissue distribution
Liver Liver, brain, placenta

20
Q

Lipoproteins are removed from the circulation by receptor mediated endocytosis

what can LDL in circulation bind to?
what will be endocytosed?
what do the vesicles bind with? what do they contain? fate of receptor?
what is there futher fusion with? why?
what could happen to receptor + apoliporprotein?

A
  1. LDLs in the circulation can bind to specific receptors expressed on endothelial cells.
  2. The receptor and LDL are endocytosed
  3. Vesicle fuses with endosomes, the endosomes contain enzymes responsible for breakdown of protein and metabolism of lipids -> receptor goes off and is re-inserted into membrane.
  4. There will be a further fusion with a lysosome to provide more enzymes, hydrolytic ones
  5. The receptor and apolipoprotein may be broken down to give amino acids, the phospholipids, FFA and triglycerides to give lipids to be used for various things and cholesterol esters can be stored and utilised
21
Q

how is the above process regulate (the uptake of cholesterol and synthesis?)

what are the 2 main mechanisms by which the receptro regulates cholesterol levels?

what does increased cholesterol in the cell do? (2)

what is a target for therapy?

A

The above process is tightly regulated, and it is regulated by the amount of cholesterol in the cell itself – the requirement of the cell for cholesterol = cholesterol regulates its own uptake and synthesis.

There are two main mechanisms by which the receptor regulates cholesterol levels, this is the amount that it uptakes and the amount the cell is making itself:

  1. LDL receptor synthesis and expression on cell surface
    - If cholesterol in the cell is elevated, cell will signal that more receptors at surface not required so the pathway is inhibited
  2. HMG-CoA reductase, rate-limiting step in cholesterol synthesis -> as cholesterol increases in cell, activity of enzyme decreases.

Cholesterol regulates its own uptake and synthesis

↑ cholesterol inhibits HMG-CoA reductase activity

↓ cholesterol ↑ LDL receptor synthesis and expression

HMG-CoA is a target for therapy

22
Q

What effect do statins have on this relationship?

what does it inhibit? what does this increase? what will this eventually lower?

A

Statins inhibit HMGCoA reductase and therefore decrease cholesterol synthesis within cells this will result in an increase in the synthesis and expression of the LDL receptor at the cell surface and so increase LDL-cholesterol uptake and therefore lowing circulating cholesterol

23
Q

other receptor interactions

apoB100 present where? (2) function?

Apo E is present where? (3) function?

A
  • ApoB100 is present on VLDL and LDLs -> Function is to bind to LDL receptor for uptake
  • Apo E is present on VLDL, HDL and chylomicrons -> function is to allow removal from circulation by specific tissues.
  • Their interactions will be tissue specific due to binding to appropriate specific receptor
24
Q

Loss of LDL Receptor Function

name the pathology and how?
what will individual have?
what are the 3 effects of this?

A

An example of a loss of LDL receptor function is Familial Hypercholesterolemia (FH). Homozygous individuals will have:

  1. High serum cholesterol
  2. As a result, develop blocked arteries (atherosclerosis)
  3. As a result, die young from heart attacks
  4. De novo synthesis is not regulated by LDL, as cell thinks it has less cholesterol

A single AA amino acid substitution that prevents localisation of the LDL receptor to the coated pits.

25
Q

Scavenger receptors

receptor?
affinity?
lipoprotein?
regulated by?
tissue distribution?
A

Receptor
SR-B1 SR-A1, SR-A2

Affinity
Low Low

Lipoprotein
HDL LDL

Regulated by
un-regulated un-regulated

Tissue distribution
endothelial cells, vsmc, macrophages (on other too)

26
Q

Scavenger receptors

what is their function?
when are they active?

regulation?

role in pathology?

A

Scavenger receptors function to take up LDL from plasma when it is elevated but are only active when circulating levels of plasma LDL are very high.

They are completely unregulated however they will continue to take up LDL independent of cellular need.

They also have a role in pathology due to the following reason:

  • The intracellular concentration of cholesterol is ultimately detrimental to the cell, short term low levels can be dealt with, but high levels cannot be dealt with and cause problems.
  • Which is why cells associated with scavenger receptors are associated with problems.
27
Q

Therapy for high LDL

how do you treat it? what two things must you do?

what are statins? how does it work?

A

Therapy for treating high cholesterol is combined, inhibiting de novo synthesis of cholesterol and inhibit absorption of cholesterol from gut.

• Statins are competitive inhibitors of HMG-CoA reductase.
o This means that they can regulate circulating cholesterol since the intracellular cholesterol levels drop, this means that the more LDL receptors will be expressed at the surface -> Reduce synthesis and circulating LDL

28
Q

Abnormalities of Lipid Transport

3 abnormalities?
what are their effects?

A

• Diabetes Mellitus:
o Increased FFA mobilisation
o Decreased chylomicron and VLDL utilisation

• Gene defects:
o Apolipoproteins, enzymes or receptors leading to hypercholesterolaemia or atherosclerosis

• Obesity:
o Hypertension, NIDDM*, hyperlipidaemia and hyperglycaemia
- noninsulin-dependent diabetes mellitus; a form of diabetes in which insulin production is inadequate or the body becomes resistant to insulin.

29
Q

Regulation of Lipoprotein is through

hormones? (3)
nutritional status? (2)
what causes ldl receptor expression?

A

Hormonal regulation:
• Insulin
• Cortisol
• Thyroid hormones

Nutritional status:
• Decreased synthesis during fasting
• Increased dietary fats – unsaturated fats

LDL receptor expression:
• Oestrogen

30
Q

Summary

A

Lipoproteins consist of triglycerides, phospholipids, cholesterol and cholesterol esters associated with proteins called apolipoproteins

Apolipoproteins act as receptors, enzymes or enzymes co-factors

Apolipoproteins also help solubilise the lipids and provide structure to the lipoprotein

Chylomicrons are formed in the gut and transport dietary lipids

VLDLs transport endogenously synthesised lipids from the liver

LDLs are a made from VLDLs and are a major cholesterol transporter

HDLs is involved in reverse cholesterol transport back to the liver and delivers cholesterol to tissues such as the testis and adrenal

MCD (22 decks)

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