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Lipid Transport Flashcards

1
Q

What are lipids

A
  • Structurally diverse group of compounds
  • Hydrophobic molecules insoluble in water = Problem for transport in blood!
  • Solution- transported in blood bound to carriers
  • ~ 2% of lipids (mostly fatty acids) carried bound to albumin but this has a limited capacity (~ 3 mmol/L)
  • ~ 98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins & TAG
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2
Q

What are different classes of lipids?

A 
Tri/di/monoacylglycerol
fatty acids
Cholesterol/cholesterol esters
Phospholipids
Vitamins A D E K
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3
Q

What are the typical plasma lipid concentration ranges?

A 
TAG: 0-2 mmol/L
Phospholipids: ~2.5 mmol/L
Total cholesterol: <5.0 mmol/L
Free fatty acids: 0.3-0.8 mmol/L
Total lipids 4000-8500 mg/L
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4
Q

Describe the structure of a phospholipid

A

Polar hydrophilic head
Phosphate
Glycerol
Non polar fatty acid tails

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5
Q

Give examples of the classification of the polar head group

A

Choline -> phosphatidylcholine

Inositol -> phosphatidylinositol

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6
Q

Wha are ways that phospholipids can be arranged?

A

Liposome - 2 layers creating a sphere, can have different environments inside and out, e.g. pH
Micelle - single layer sphere
Bilayer sheet - e.g. membranes

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7
Q

Where is cholesterol obtained/synthesised?

A

Some obtained fromdiet but most synthesised in liver

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8
Q

What is cholesterol used for?

A
  • Essential component of membranes (modulates fluidity)
  • Precursor of steroid hormones
  • Cortisol
  • Aldosterone
  • Testosterone
  • Oestrogen
  • Precursor of bile acids (produced in liver stored in GB released into GI)
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9
Q

How is cholesterol transported around the body?

A

As cholesterol ester. OH group esterified with fatty acid (R) to OCOR group by enzymes LCAT or cholesterol acyltransferase

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10
Q

What are lipoproteins?

A

Phospholipid monolayer with small amount of cholesterol
Peripheral apolioproteins (apoC, apoE) and Integral Apolipoproteins (apoA, apoB)
Has cargo inside
- TAG, Cholesterol ester, Vit ADEK

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11
Q

What are the 5 distinct classes of lipoproteins according to density?

A
  • Chylomicrons
  • VLDL (Very Low Density Lipoproteins)
  • IDL (Intermediate Density Lipoproteins)
  • LDL (Low Density Lipoproteins
  • HDL (High Density Lipoproteins)

If VLDL become depleted they become IDL, if these deplete they become LDL etc etc

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12
Q

Which classes of lipoproteins are carriers of fat and which are carriers of cholesterol ester

A

• Each contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester

Chylomicrons And VLDL are main carriers of fat
IDL, LDL And HDL are main carriers of cholesterol ester

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13
Q

How is density of lipoproteins obtained and how is particle diameter related to density?

A

Sucrose gradient to separate proteins out
Higher density migrate further in sucrose gradient
• Density obtained by flotation ultracentrifugation
• Particle diameter inversely proportional to density

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14
Q

Which class of lipids are the most/least dense

A

(Most dense/smallest diameter) HDL -> LDL -> IDL -> VDL -> chylomicron (least dense/largest diameter)

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15
Q

When are chlomicrons normally present in blood

A

4-6 hours after a meal

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16
Q

What are apolipoproteins?

A
  • Each class of lipoprotein particle has a particular essential complement of associated proteins (apolipoproteins) • Six major classes (A,B,C,D,E & H)
  • apoB (VLDL,IDL &LDL) and apoAI (HDL) important
  • Apolipoproteins can be integral passing through phospholipid bilayer or peripheral “resting” on top
17
Q

What are the 2 roles of apolipoproteins?

A

Structural:
Packaging water insoluble lipid

Functional:
Co-factor for enzymes
Ligands for cell surface receptors

18
Q

Describe chylomicron metabolism

A
  • Chylomicrons loaded in small intestine and apoB-48 added before entering lymphatic system
  • Travel to thoracic duct which empties into left subclavian vein and acquire 2 new apoproteins (apoC and apoE) once in blood.
  • apoC binds lipoprotein lipase (LPL) on adipocytes and muscle. Released fatty acids enter cells depleting chylomicron of its fat content.
  • When triglyceride reduced to ~ 20%, apoC dissociates and chylomicron becomes a chylomicron remnant
  • Chylomicron remnants return to liver. LDL receptor on hepatocytes binds apoE & chylomicron remnant taken up by receptor mediated endocytosis . Lysosomes release remaining contents for use in metabolism

Dietary fat at acted on pancreatic lipase
Tag broken apart and put together inside chylomicrons

ApoB 48% of normal size = premature stop codon
LDL reconises apoB100 but not apoB48

ApoC allows chyloicron to bind to lipoprotein lipase - allows tissues to utilise fat inside

See slide for diagram

19
Q

Describe VLDL metabolsim

A

• VLDL made in liver for purpose of transporting
triacylglycerol (TAG) to other tissues.
• Apolipoprotein apoB100 added during formation and apoC and apoE added from HDL particles in blood.
• VLDL binds to lipoprotein lipase (LPL) on endothelial cells in muscle and adipose and starts to become depleted of triacylglycerol
• In muscle the released fatty acids are taken up and used for energy production
• In adipose the fatty acids are used for re-synthesis of triacylglycerol and stored as fat

20
Q

Describe IDL and LDL metabolism

A

Formation
• VLDL -> IDL -> LDL
• As triacylglycerol content of VLDL particles drops some, VLDL particles dissociates from the LPL enzyme complex and return to liver
• If VLDL content depletes to ~30%, the particle becomes a short-lived IDL particle.
• IDL particles can also be taken up by liver or rebind to LPL enzyme to further deplete in TAG content
• Upon depletion to ~ 10%, IDL loses apoC & apoE and becomes an LDL particle (high cholesterol content)
High ldl - link to chd - promote formation of plaques

21
Q

What is the primary function of LDL

A
  • Primary function of LDL is to provide cholesterol from liver to peripheral tissues.
  • Peripheral cells express LDL receptor and take up LDL via process of receptor mediated endocytosis
  • Importantly, LDL do not have apoC or apoE so are not efficiently cleared by liver (Liver LDL-Receptor has a high affinity for apoE).
22
Q

What is the clinical relevance of LDL metabolism?

A
  • Half life of LDL in blood is much longer than VLDL or IDL making LDL more susceptible to oxidative damage
  • Oxidised LDL taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques
23
Q

Give an overview of where VLDL IDL and LDL metabolism takes place

A

See slide for diagram

24
Q

How do LDLs enter cells?

A

• Cells requiring cholesterol express LDL receptors on plasma membrane
• apoB-100 on LDL acts as a ligand for these receptors
• Receptor/LDL complex taken into cell by endocytosis into
endosomes
• Fuse with lysosomes for digestion to release cholesterol and fatty acids
• LDL –R expression controlled by cholesterol concentration in cell

25
Describe HDL synthesis
* Nascent (empty) HDL synthesised by liver and intestine (low TAG levels) * HDL particles can also “bud off” from chylomicrons and VLDL as they are digested by LPL * Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL
26
Describe HDL maturation
* Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels * Hollow core progressively fills and particle takes on more globular shape * Transfer of lipids to HDL does not require enzyme activity
27
What is reverse cholesterol transport?
* HDL have ability to remove cholesterol from cholesterol-laden cells and return it to liver * Important process for blood vessels as it reduces likelihood of foam cell and atherosclerotic plaque formation * ABCA1 protein within cell facilitates transfer of cholesterol to HDL. Cholesterol then converted to cholesterol ester by L C AT
28
What is the ate of mature HDL?
* Mature HDL taken up by liver via specific receptors • Cells requiring additional cholesterol (e.g. for steroid hormone synthesis) can also utilise scavenger receptor (SR-B1) to obtain cholesterol from HDL * HDL can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
29
Give an overview of HDL metabolism
See slide
30
What is the transport function of each class of lipoprotein?
Chylomicrons - transport dietary triacylglycerol from the intestine to tissues such as adipose tissue VLDL - transport of triacylglycerol synthesised i liver to adipose tissue for storage IDL - short lived precursor of LDL. Transport of cholesterol synthesised in the liver to tissues LDL - transport of cholesterol synthesised in liver to tissues HDL - transport of excess cholesterol from cells to liver or disposal as bile salts and to cells requiring additional cholesterol
31
What are hyperlipoproteinaemias?
Raised plasma level of one or more lipoprotein classes Caused by either: 1. Over-production 2. Under-removal 6 main classes Defects in: • Enzymes • Receptors • Apoproteins
32
What are the 6 classes of hyperlipoproteinaemias?
I - chylomicrons in fasting plasma. No link with coronary artery disease. Caused by defective LIPOPROTEIN LIPASE IIa- associated with coronary artery disease that may be severe. Caused by defective LDL receptor IIb - Associated with coronary artery disease. Defect unknown III - Reaised IDL and chylomicron remnants. Associated with coronary artery disease. Rare (1 in 10000) Caused by defective APOPROTEIN (apoE) IV - Associated with coronary artery disease, defect unknown. V - raised chylomicrons and VLDL in fasting plasma. Associated with coronary artery disease. Cause unknown.
33
What are clinical signs of hypercholesterolaemia
* High level of cholesterol in blood * Cholesterol depositions in various areas of body * Xanthelasma - Yellow patches on eyelids * Tendon Xanthoma - Nodules on tendon * Corneal arcus - obvious white circle around eye. Common in older people but if present in young could be a sign of hypercholesterolaemia
34
What is raised serum LDL associated with
Atherosclerosis - Oxidised LDL - Recognised and engulfed by macrophages - Lipid landed macrophages called FOAM CELLS accumulate in intima of blood vessel walls to form a fatty streak - Fatty streak evolves into atherosclerotic plaque - grows and encroaches on the lumen of the artery (can lead to angina) - Ruptures - Triggers acute thrombosis by activating platelets and clotting cascade - can lead to stroke or myocardial infarction
35
Describe plaque formation
``` See slide for diagram Signalling pathways cause smooth muscle layer to proliferate Not as much blood down arteriolr Plaque grows Angina ``` If plaque ruptures - thrombus forms Can cause stroke or heart attack
36
What is the first response treatment for hyperlipoproteinaemias
Diet • Reduce cholesterol and saturated lipids in diet. Increase fibre intake. Lifestyle • Increase exercise • Stop smoking to reduce cardiovascular risk
37
Howe are hyperlipoproteinaemias treated if there is no response to drugs
Statins • Reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin Bile salt sequestrants • Bind bile salts in GI tract. Forces liver to produce more bile acids using more cholesterol e.g. Colestipol
38
How do statins work
Inhibit HMG-CoA reductase Inhibit pathway to cholesterol formation from Acetyl-CoA Statins have side effects - enzymes high up in pathway - a lot of intermediates affected Targeted drug in lower steps in future possibly As this affects entire pathway - could explain statins side effects
39
What are ideal cholesterol levels
• Total Cholesterol (TC) Ideally 5 mmol/L or less • Non HDL-Cholesterol (total cholesterol minus HDL-cholesterol) Ideally 4mmol/L or less • LDL-Cholesterol (LDL-C) Ideally 3 mmol/L or less • HDL-Cholesterol (HDL-C) Ideally over 1mmol/L (men) and over 1.2mmol/L (women). • Total cholesterol:HDL-C ratio Ratio above 6 considered high risk - the lower the ratio the better. • Triglyceride (TG) Ideally < 2mmol/L in fasted sample

MEH (21 decks)

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