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ESA 2 - MEH > 4. Lipid transport > Flashcards

4. Lipid transport Flashcards

1
Q

Name the various classes of lipids and their concentration in blood.

A
  1. triacylglycerols (+ diacylglycerols and monoacylglycerols) - 1.0 mmol/L
  2. phospholipids - 2.5 mmol/L
  3. cholesterol - 1.5 mmol/L, and cholesterol esters (cholesterol + fatty acid) - 3.5 mmol/L
  4. free fatty acids - 0.4 mmol/L
  5. vitamins A, D, E and K

Total lipids = 4,000-8,500 mg/L

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2
Q

How are lipids transported in blood?

A

Hydrophobic molecules insoluble in water so transported bound to carrier proteins:
~2% (mostly fatty acids released from adipose tissue by lipolysis to use as fuel in tissues) carried non-covalently bound to albumin (but has limited capacity, <3 mmol/L)
~98% carried as lipoprotein particles (consisting of phospholipids, cholesterol, cholesterol esters, proteins and TAGs)

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3
Q

Describe the structure of a phospholipid. How are these classified?

A
  • Hydrophilic head consisting of: polar head group + phosphate + glycerol
  • Hydrophobic non-polar tail consisting of 2 saturated or unsaturated fatty acids

Classified according to polar head group, e.g. choline = phosphatidylcholine, inositol = phosphatidylinositol

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4
Q

Where to we obtain cholesterol?

A
  • some obtained from diet

- most synthesised in liver (300mg/day)

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5
Q

Why is cholesterol essential for life?

A
  1. essential component of cell membranes (modulates fluidity)
  2. precursor of steroid hormones - cortisol, aldosterone, testosterone and oestrogen
  3. precursor of bile acids
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6
Q

How is cholesterol transported around the body?

A

As cholesterol ester - esterified with a fatty acid by LCAT or acyl-coenzyme A

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7
Q

What are plasma lipoprotein particles?

A

Spherical multi-molecular complexes containing variable amounts of different lipids in non-covalent (mostly hydrophobic) association with specific apoproteins.

Primary function is to transport water-insoluble lipid molecules in the bloodstream.

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8
Q

Describe the structure of a lipoprotein particle.

A
  1. Spherical surface coat consisting of:
    - phospholipid monolayer
    - small amount of cholesterol
    - peripheral (apoC, apoE) and integral (apoA, apoB) apolipoproteins
  2. Hydrophobic core/cargo:
    - traglycerol
    - cholesterol ester
    - fat-soluble vitamins (A, D, E and K)
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9
Q

What are the 5 classes of plasma lipoproteins? How do these differ?

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

Differ in relative amount of lipid type and apoprotein composition - different physical properties, e.g. density.

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10
Q

What does the removal of lipids from chylomicrons or VLDLs form?

A

Lipid removal from:

  • chylomicrons forms chylomicron remnants
  • VLDL leads to sequential generation of IDL and LDL particles
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11
Q

How is lipoprotein density determined? What is the appearance of centrifuged serum containing chylomicrons?

A
  • Flotation ultracentrifugation

- Presence of chylomicrons (only present in blood 4-6 hrs after meal) = “creamy” appearance

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12
Q

What is lipoprotein density determined by? Which type has the highest density?

A

Surface to volume ratio - particle diameter inversely proportional to density.

From most dense (high % protein):

  • HDL (5-15 nM)
  • LDL (18-28 nM)
  • IDL (25-30 nM)
  • VLDL (30-80 nM)
  • chylomicrons (100-1000 nM)
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13
Q

What are the different structures and types of apolipoproteins?

A

2 structures:

  • integral (pass through phospholipid bilayer)
  • peripheral (rest on top of bilayer)

6 major classes: A, B, C, D, E and H.
apoB (VLDL, IDL, LDL) and apoAI (HDL) are important.

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14
Q

What are the roles of apolipoproteins?

A
  1. Structural
    - packaging water-insoluble lipid
  2. Functional
    - co-factor for enzymes (activating)
    - ligands for cell surface receptors (e.g. LDL Rs)
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15
Q

What are the transport functions of the different lipoprotein types?

A
  1. chylomicrons - transport dietary TAG from intestine to tissues such as adipose tissue
  2. VLDL - transport TAG synthesised in liver to adipose tissue for storage
  3. IDL - short-liver precursor for LDL. transport of cholesterol synthesised in the liver to tissues.
  4. LDL - transport of cholesterol synthesised in liver to tissues.
  5. transport of excess tissue cholesterol to liver for disposal as bile salts and to cells requiring additional cholesterol
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16
Q

Which enzyme mediates lipoprotein catabolism? Where is it found?

A
  • Lipoprotein lipase: removal of core TAGs from lipoprotein particles (such as chylomicrons and VLDLs) via TAG hydrolysis into fatty acids (taken up by tissues) and glycerol (transported to liver).
  • Found attached to inner surface of capillaries in tissues such as adipose and muscle.
17
Q

What are the functions of LCAT?

A
  1. lipoprotein formation

2. lipoprotein structure maintenance

18
Q

Which process decreases the stability of lipoproteins and how is this stability restored?

A

Unstable due to removal of core lipids from lipoproteins as ration of surface to core lipids increases.

Stability restored by conversion of some surface lipid to core lipid via LCAT: converts cholesterol to cholesterol ester using fatty acids derived from leicithin (phosphatidylcholine).

19
Q

What is the effect of insulin on lipoprotein lipase?

A

insulin increases synthesis of lipoprotein lipase by tissues

20
Q

Describe the process of chylomicron metabolism, including the addition/removal of apolipoproteins.

A
  1. Synthesised in small intestine epithelial cells (packaged with dietary TAG, cholesterol and fat-soluble vitamins) - apoB-48 added.
  2. Enters lymphatic system and travels to thoracic duct which empties into left subclavian vein. Acquires apoC and apoE once in blood.
  3. apoC binds lipoprotein lipase (LPL) on adipocytes and muscle.
  4. Lipoprotein lipase (requries apoC-II as co-factor) in capillaries of these tissues hydrolysis TAGs - released fatty acids enters tissue cells, depleting chylomicron of its fat content.
  5. When triglyceride reduced to ~20%, apoC dissociates - chlyomicron becomes chylomicron remnant.
  6. Chylomicron remnants return to liver. LDL receptors on hepatocytes bind apoE - remnant uptake by receptor-mediated endocytosis.
  7. Lysosomes release remaining contents for use in metabolism.
21
Q

What is special about the encoding of apoB-48?

A

same gene as apoB-100 but intestinal epithelial cells perform RNA editing: add premature stop codon to apoB-100 mRNA so only 48% of length.

22
Q

Where does VLDL synthesis occur and which apolipoproteins are added?

A

Synthesised in liver - addition of apoB100.

apoC and apoE added from HDL particles in blood.

23
Q

How does VLDL become depleted of TAG?

A
  • Binds to lipoprotein lipase (LPL) on endothelial cells in muscle and adipose - TAG hydrolysis and fatty acid release.
  • Released FAs taken up and used for energy production in muscle, or re-synthesised as TAG and stored as fat in adipose.
24
Q

What happens to VLDL particles as TAG content drops?

A

1- Some VLDL particles dissociate from LPL enzyme complex and return to liver.
2- If VLDL content depletes to ~30%, it becomes a short-lived IDL particle.
3- IDL can also be taken up by liver, or rebind LPL enzyme to further deplete in TAG content.
4- Upon depletion to ~10%, IDL loses apoC and apoE and becomes LDL particle (high cholesterol content).

25
Q

What is the primary function of LDL?

A

provide cholesterol from liver to peripheral tissues

26
Q

How does LDL deliver cholesterol to peripheral cells that require it?

A

i) Peripheral cells requiring cholesterol specifically express LDL receptor… bind to apoB-100… take up LDL via receptor-mediated endocytosis…
ii) lysosomal digestion of LDL and conversion of cholesterol esters to free cholesterol released inside the cell…
iii) cholesterol can be stored (as cholesterol esters) or used.

27
Q

How is the accumulation of too much cholesterol by peripheral cells prevented?

A

receptor mediated uptake of LDL:
1- inhibits cellular synthesis of cholesterol
2- reduces synthesis and exposure of LDL Rs

28
Q

What is the function of HDL?

A

Transport excess cholesterol from tissues to the liver for disposal as bile salts, or to other cells requiring additional cholesterol - have a hollow core which progressively fills as particle accumulates phospholipid and cholesterol from cells, e.g. lining blood vessels (doesn’t require enzyme activity).

29
Q

Why is HDL important for health?

A

Removal of excess cholesterol from BV cells important in reducing likelihood of foam cell and atherosclerotic plaque formation

30
Q

How are HDL particles synthesised?

A

1- nascent HDL with low TAG content are synthesised by liver and intestine
2- some HDL can also “bud off” from chylomicrons and VLDL as they are digested by LPL
3- free apoA-I can also acquire cholesterol and phospholipids from other lipoproteins and cells membranes to form nascent-like HDL

31
Q

By which process is cholesterol moved in HDL particles?

A

Reverse cholesterol transport facilitated by ABCA1 protein. Cholesterol then converted to cholesterol ester by LCAT.

32
Q

What is the fate of mature HDL?

A

1- taken up by liver via specific receptors
2- cells requiring additional cholesterol can utilise scavenger receptor (SR-B1) to obtain cholesterol from HDL
3- HDL can exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)

33
Q

Why cell type is likely to require additional cholesterol?

A

steroidogenic cells require cholesterol for steroid hormone synthesis

34
Q

What is the consequence of the poor clearance of LDL particles by the liver?

A

1/2 life of LDL is much longer than VLDL or IDL - more susceptible to oxidative damage which can lead to atherosclerosis and consequent angina, MI or stroke

35
Q

How does oxidative damage of LDL lead to angina, MI or stroke?

A
  1. oxidised LDL recognised and engulfed by macrophages.
  2. lipid-laden macrophages - foam cells - accumulate in intima of BV walls to form a fatty streak.
  3. fatty streaks can evolve into atherosclerotic plaque.
  4. plaque grows and encroaches on lumen of artery…
    a) angina if occlusion of coronary artery
    b) rupture of plaque triggers acute thrombosis (clot) by activating platelets and clotting cascade… stroke (brain) or MI (coronary artery)

ESA 2 - MEH (42 decks)

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