W6 Lipid transport

Question 1

Lipids are transported from

Answer 1

The gut to the liver

The liver to non-hepatic tissue including adipocytes

Non-hepatic tissue back to the liver

Question 2

How are lipoproteins characterised

Answer 2

By how they behave in density centrifugation and density dependent on composition

Question 3

Free fatty acids

Answer 3

Formed from triacylglycerides stored in adipose tissue

Circulates bound to protein as Na+ salt particularly albumin as unbound FA would act as a detergent

Saturation occurs at about 2mM FA molecules

FA enter cells by simple diffusion

Intracellular con centration FFA kept low so detergents

Question 4

Lipoprotein

Answer 4

Orientated same as in plasma membrane

Hphobic inwards

Hphilic outwards

Do not form bilayers as no Hphobic core as single layer

Km of LPL isoform in adipocytes
greater than muscle

LPL on adipocytes are
stimulated by insulin

Question 5

Apolipoproteins function

Answer 5

Structural

To solubilise lipids

Synthesised on SER + released into lymph + interact w/HDL

Act as enzymes or enzyme cofactors:
Apo C2 for lipoprotein lipase
Apo A1 for lecithin: cholesterol acyltransferase

Tissue targeting:
Apo B100 and Apo E bind to the LDL receptor
Apo E binds to the HDL receptor

Question 6

Dietary lipids

Answer 6

Low density due to high TG

Apo C2, C3, E and B48 added in the SER

Secreted by reverse pinocytosis in to the lymphatics (delivered to non-hepatic tissue first + drained into thorasic duct + not in blood)

Question 7

Mature chylomicrons

Answer 7

HDL donate APOC2 and ApoE to form mature chylomicrons

Question 8

Chylomicrons

Answer 8

Reflects meal composition

Low density due to high TG

Also contain fat soluble vitamins
Vitamins A and E

Life time in the circulation of 1h (TG 5mins)

Remnants (large proteins) removed by the liver with the involvement of Apo E

Question 9

Vitamin E

Answer 9

Important antioxidant preventing oxidation of lipids which are associated with heart disease.

Question 10

Vitamins

Answer 10

Inhibit oxidation of lipids w/in them. Prevents deposition of fats in certain tissues

Question 11

Type 1 hyperlipidaemia

Answer 11

Deficiency in lipoprotein lipase or Apo C2 – characterised by high plasma triglyceride

Question 12

Type 2 hyperlipidaemia

Answer 12

Characterised by high LDL – most caused by a genetic defect in the synthesis processing or function of the LDL receptor

Question 13

Type 4 hyperlipidaemia

Answer 13

Most common results in increased VLDL concentrations often due to obesity or alcohol abuse

Question 14

VLDL

Answer 14

Synthesised in the liver ER and golgi released with B100 then acquire Apo E and C from HDL

Metabolised by LPL as they circulate - TG half-life of 15-60 mins

Larger than chylomicrons

Formation enhanced by

1) dietary carbohydrate
2) circulating FFA
3) alcohol
4) raised insulin and decreased glucagon

Remnant removed by the liver by apoE (TG 15-60 mins)

Question 15

B48

Answer 15

Shortened version of B100 + B48 not made in liver

Question 16

VLDL change in structure when [TGL] low

Answer 16

High in CL, low in TGL
Deliver CL to non-hepatic tissue
Removed from circulation when passed through liver

Question 17

LDL

Answer 17

Are the major carrier of cholesterol

Metabolised slowly - 3 days

Carry cholesterol to the periphery and regulate de novo synthesis

Contain 1 ApoB100 which can bind to a specific receptor on hepatocytes

Question 18

VLDL remnants

Answer 18

60% 0f VLDL remnants are removed by the liver
40% removed by adrenal and gonadal tissue and the cholesterol is used for hormone production. Both use the ApoB100 to bind to the LDL receptor.
If there is two much LDL the receptors are saturated the excess can be removed via a low affinity scavenger receptor

Question 19

High density lipoproteins HDL

Answer 19

Circulating reservoir of apolipoproteins (C2 and apo E)

Apolipoproteins are also obtained from VLDLs and chylomicrons

Remove cholesterol from the plasma

They contain the enzyme lecthin cholesterol acyltransferase (LCAT) which esterifies cholesterol (traps CL w/in HDL)

Transported to liver and steroid producing cells

HDL binds to lipoproteins and cells via apoE this is important for cholesterol transfer

They return cholesterol to the liver but also transfer it to VLDLs and LDLs – cholesterol ester transfer protein

Question 20

HDL made …

Answer 20

In the liver and intestine
By budding from VLDL and Chylomicrons
From free apoA1 (form spontaenously)

Question 21

ABCA1

Answer 21

Enable transfer of CL from membrane to HDL then transported to the liver

Question 22

Receptor mediated endocytosis

Answer 22

LDL binds to receptor in pit

RM endocytosis takes place

Endosome w/LDL fuses w/lysosome (hydrolytic enzymes)

W/in endosome the receptors + LDLs dissociate

Question 23

How CL trapped

Answer 23

Esterified then desterified to trapped CL w/in cell

Question 24

What regulates cholesterol uptake and synthesis?

Answer 24

Cholesterol regulates its own uptake and synthesis

↑ cholesterol inhibits HMG-CoA reductase activity

↓ cholesterol ↑ LDL receptor expression

HMG-CoA is a target for therapy

Question 25

What effect does an increase in HMG CoA reductase have on the level of expression of LDL receptors?

Answer 25

The synthesis of the LDL receptor and its expression at the cell surface is negatively regulated by the intracellular concentration of cholesterol. When the intracellular concentration of cholesterol decrease the synthesis of cholesterol from acetyl-CoA and the LDL receptor increase. HMGCoA reductase is the rate limiting step in the synthesis of cholesterol

Question 26

What effect do statins have on this relationship?

Answer 26

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

Question 27

How do statins work?

Answer 27

Stains inhibit HMGCoA reductase

Low intracellular Cholesterol increases LDL receptor at the cell surface

Leading to increase uptake of LDL

Lower circulating LDL

Question 28

LDL (affinity…)

Answer 28

Affinity:
High

Present on:
VLDL + LDL

Binds to:
ApoB100

Regulated by:
CL

Tissue distribution:
Liver

Question 29

LDL-like (affinity…)

Answer 29

Affinity:
High

Present on:
VLDL + HDL, chylomicron

Binds to:
ApoE

Regulated by:
CL

Tissue distribution:
Liver

Question 30

Scavenger (affinity…)

Answer 30

Affinity:
Low

Present on:
LDL

Regulated by:
Un-regulated

Tissue distribution:
Endothelial cells
Macrophages

Question 31

Scavenger receptor

Answer 31

Present on
Endothelial cells
Macrophages
VSMC

Low affinity active when plasma LDL high or oxidised

Not regulated by cholesterol

Question 32

Foam cell

Answer 32

Macrophage which has lost its normal function

Stack in vessel wall

Question 33

Familial Hypercholesterolemia (FH)

Answer 33

Homozygous individuals:

1. High serum cholesterol (800mg/ml, normal is 200mg/ml)
2. Develop blocked arteries (atherosclerosis)
3. Die young from heart attacks
4. De novo synthesis is not regulated by LDL

Single amino acid substitution that prevents localisation of the LDL receptor to the coated pits

Low affinity active when plasma LDL high or oxidised.

Not regulated by cholesterol