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BIOM30001 - Frontiers in Biomedicine > Lecture 7 - Lipids in Health and Disease > Flashcards

Lecture 7 - Lipids in Health and Disease Flashcards

1
Q

Describe the structure of LDL

A
  • Core:
    • Esterified cholesterol
    • TAGs
  • Coat:
    • ApoB-100
    • Phospholipid monolayer
    • Free cholesterol (unesterified)
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2
Q

What are the various lipoprotein classes?

A
  • Chylomicrons
  • VLDL
  • LDL
  • IDL
  • HDL
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3
Q

Describe the correlations with the various classes of lipoprotein and CVD

A
  • High LDL correlates with high risk of CVD
  • High HDL correlates with low risk of CVD
  • Ratio of total cholesterol / HDL:
    • Increased ratio correlates with increased risk
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4
Q

When are total cholesterol levels ‘too high’?

A

After around 5 mM CVD risk rises significantly

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5
Q

Describe the structure of chylomicrons

A
  • Core:
    • TAGs
    • Cholesteryl esters
  • Coat:
    • Phospholipid monolayer
    • Apoproteins:
      • B-48, C-II, C-III
    • Cholesterol
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6
Q

What are cholesteryl esters?

A
  • Esterified cholesterol
  • Polar group (-OH) has been removed and replaced with an acyl group
  • These are the cholesterol molecules present in the core of lipoprotein molecules
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7
Q

Where are chylomicrons formed?

A

In the intestinal mucosa from dietary lipids

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8
Q

Compare the apoproteins found in the following:

  • Chylomicrons
  • VLDL
  • IDL
  • LDL
A
  • Chylomicrons:
    • ApoB-48
    • ApoC-II
    • ApoC-III
  • VLDL:
    • ApoB-100
    • ApoE
    • ApoC-II
  • IDL:
    • ApoB-100
    • ApoE
  • LDL:
    • ApoB-100
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9
Q

Compare the following features in the various classes of lipoprotein:

  • Density
  • Protein content
  • TAG content
  • Cholesterol content
A
  • Density (lowest to highest)
    • CM → VLDL → LDL → HDL
  • Protein content:
    • CM → VLDL → LDL → HDL
  • Cholesterol content:
    • ​CM → HDL → LDL & VLDL
  • TAG content
    • HDL → LDL → VLDL → CM
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10
Q

What are the three stages of lipid transport?

Give a brief overview of each

A
  1. Exogenous pathway:
    • Uptake of dietary TAGs in intestine, delivery to adipose cells and liver
  2. Endogenous pathway
    • Transport of cholesterol from liver to tissues
  3. Reverse cholesterol transport
    • Recycling of cholesterol from macrophages / foam cells in artery walls back to liver
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11
Q

Compare TAG and TGs

Describe their structures

A
  • These are the same thing
    • TAG: Triacylglycerol
    • TG: Triglyceride
  • Structure:
    • Glycerol backbone
    • Three fatty acids
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12
Q

Outline exogenous lipid transport

A
  1. Digestion:
    1. Bile salts emulsify dietary lipids
    2. Lipases degrade TAGs into:
      • FFAs
      • Glycerol
      • Monoglycerides
      • Di-glycerides
  2. Absorption
    1. FFAs and glycerol taken up into enterocytes
    2. FFAs and glycerol are converted back into TAGs
    3. TAGs incorporated into CMs with apoproteins
    4. CMs taken up into lacteals and move into lymphatics
  3. CMs drain into circulation at thoracic duct
  4. Lipoprotein lipase digests TAGs back into FFAs and glycerol
  5. Storage
    1. FFAs enter cells (myocytes or adipocytes)
    2. FFAs are oxidised for energy of stored as TAGs
  6. CM remnants (depleted of TAGs) circulate to the liver and are taken up by RME
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13
Q

Describe endogenous lipid transport

A
  1. Cholesterol and TAGs are packaged into VLDL with ApoB-100 (acting like a scaffold) in hepatocytes
  2. VLDL circulate in blood where ApoE and ApoC-II are incorporated
  3. Lipoprotein lipase digests TAGs to FFA
  4. FFAs taken up into tissues:
    • Myocytes (for oxidation)
    • Adipocytes (for storage as TAGs)
    • Gonads
    • Adrenal glands
  5. VLDL depleted of TAGs and C, and have lost ApoC-II are now IDL
  6. Released ApoC-II activates lipoprotein lipase (which plays a role at step 3.)
  7. 50% of IDL taken back up by hepatocytes
    • Through LDLR which binds ApoE
  8. 50% of IDL loses ApoE and undergoes further lipolysis to become LDL
  9. 70% LDL taken up LDLR into hepatocytes
  10. Other LDL taken up by extra hepatic tissue
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14
Q

Describe reverse cholesterol transport (RCT)

A
  1. HDL produced in blood
  2. HDL picks up excess free cholesterol from artery walls
  3. Cholesterol converted to CE
  4. HDL recirculates back to liver
  5. HDL binds SR-B1 on hepatocytes, transferring its cargo to the cells
  6. CE excreted by liver in bile
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15
Q

Where is VLDL synthesised?

Describe its synthesis

A
  • In the ER of hepatocytes:
    • ApoB-100:
      • Acts as a scaffold
      • Has binding sites for MTP: microsomal transfer protein
      • MTP is necessary for the assembly of VLDL
    • VLDL then enters circulation, where it associates with:
      • ApoE
      • ApoC-II
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16
Q

What is an atheroma?

Describe its structure

A
  • The fibro-fatty plaque formed by atherosclerosis
  • Core: fatty material
  • Cap: fibrous
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17
Q

Where is HDL produced?

A

In the blood

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18
Q

Describe the process of synthesis of HDL

A
  1. ApoA-1 & phospholipid disc produced in liver
  2. In blood, free cholesterol is esterified to CE which combines with the disc to form HDL2
    • Esterification performed by LCAT
  3. CE exchanged for TAG to form HDL3
    • Exchange performed by CETP
    • TAGs are coming from VLDL and LDL
19
Q

Compare HDL2 and HDL3

A

HDL2: larger

HDL3: smaller

20
Q

Compare CETP and LCAT

A
  • LCAT:
    • Converts C to CE in HDL2
  • CETP:
    • Exchanges CE in HDL for TAGs from LDL and VLDL
21
Q

List some factors that affect blood cholesterol

A
  • Modifiable:
    • Diet
    • Exercise
    • Smoking
    • Weight
  • Non-modifiable:
    • Age
    • Gender
    • Genetics
22
Q

Describe how the following affect blood C

  • Diet
  • Weight
  • Smoking
  • Exercise
  • Age
  • Gender
  • Genetics
A
  • Diet:
    • High sat-fat diet correlates to high blood C
  • Weight:
    • Overweight and obesity correlate to high blood C
    • Weight loss can decrease LDL and increase HDL
  • Smoking:
    • Smoking correlates to high blood C
  • Exercise:
    • Exercise can reduce LDL and increase HDL
  • Age:
    • Blood C increases with age
  • Gender:
    • Women have lower blood C until 55, then they catch up
  • Genetics
    • A handful of rare mutations can cause v. high blood C
    • Familial hypercholesterolaemia; LDLR mutation
    • Apo B mutation
    • Apo E mutation
23
Q

List some factors that affect blood TAGs

A
  • Acquired:
    • Insulin resistance
    • Obesity
    • DM
    • Excess alcohol
    • Hypothyroidism
    • Medication
  • Primary:
    • Genetics
24
Q

Describe the effect of diabetes on TG production and clearance

A

Production: ↑↑

Clearance: ↓

25
Q

Describe the effect of obesity on TG production and clearance

A

Production: ↑↑

Clearance: ↓/-

26
Q

Describe the effect of excess alcohol on TG production and clearance

A

Production: ↑↑

Clearance: ↓/-

27
Q

Describe the effect of hypothyroidism on TG production and clearance

A

Production: ↑

Clearance: ↓

28
Q

Describe the effect of beta blockers on TG production and clearance

A

Production: ↑

Clearance: ↓

29
Q

Describe the effect of immunosuppressants on TG production and clearance

A

Production: ↑↑

Clearance: -

30
Q

Describe the effect of protease inhibitors on TG production and clearance

A

Production: -

Clearance: ↓

31
Q

Describe the effect of oestrogen replacement on TG production and clearance

A

Production: ↑

Clearance: -

32
Q

Describe genetic influences of blood TG levels

A

All rare mutations:

  • ApoB-100
  • Lipoprotein lipase
  • ApoC-II
33
Q

Which molecule activates LPL?

A

(Lipoprotein lipase) ApoC-II

34
Q

Define the following:

  • Hypertriglyceridaemia
  • Hyperglycaemia
  • Hypercholesterolaemia
A
  • Hyperglycaemia
    • Increased blood levels of glucose in blood
  • Hypertriglyceridaemia:
    • Increased TAGs in blood
  • Hypercholesterolaemia:
    • Increased total cholesterol (C + CE) in blood
35
Q

Describe the features of dyslipidaemia in the metabolic syndrome

A
  • LDL changes:
    • LDL-C levels normal
    • LDL-C particles have altered structure
      • Small
      • Dense
      • Triglyceride-rich
      • Glycated
    • This makes the LDL particles particularly atherogenic
  • HDL:
    • Decreased HDL-C levels
    • Increased HDL catabolism
      • Due to:
      • Hypertriglyceridaemia
      • Glycation of HDL particles
36
Q

Describe why there is decreased HDL in T2DM and the MS

A
  1. Hypertriglyceridaemia
  2. Increased TAGs in HDL
    • Making it a better substrate for hepatic lipase
  3. Hepatic lipase degrades HDL
  4. Also:
    • Increased glycation of HDL could interfere with HDL efflux from cells and RCT
37
Q

What are the beneficial properties of HDL?

A
  • Anti-inflammatory
  • Anti-oxidative
  • Anti-thrombotic
  • Acts as vasorelaxant on endothelium
38
Q

Describe the pathogenesis of atherosclerosis

A
  1. Damage to endothelium of arteries
    • ox-LDL
    • Smoking
    • Infection
    • High BP
  2. Increased expression of adhesion molecules on endothelium
    • P-selectin
    • MCP-1
    • MCSF
  3. Adhesion of monocytes and migration into artery intima, differentiation into macrophages
  4. Movement of LDL into intima of arteries in response to changes taking place in the wall
  5. LDL oxidation: LDL → ox-LDL
  6. LDL taken up by macrophages by SR receptors in an aberrant way → foam cells
  7. Further oxidation of LDL ox-LDL → highly ox-LDL
  8. Aberrant GF signalling recruits SMCs to intima
  9. Formation of fatty streak in artery wall
  10. Formation of atheroma
  11. If atheroma is unstable, rupture can lead to formation of thrombi which can occlude vessels
  12. Continuous growth of atheroma can cause critical stenosis
39
Q

How is LDL taken up by macrophages in the intima of the artery wall?

A

ox-LDL binds to SR (scavenger receptors) on macrophages

40
Q

How is HDL normally collected from macrophages?

A

Excess HDL moves out of macrophages in the intima wall of the artery back into circulation

41
Q

What are MCP-1 and MCSF?

A
  • MCP-1: monocytes chemoattractant protein
  • MCSF: Macrophage colony stimulation factor
42
Q

What happens when there is damage to the endothelium of arteries?

A
  • Adhesion and migration of monocytes
  • Increased uptake of LDL and production of ox-LDL
43
Q

How does LDL become oxidised in the intima of arteries?

A

Oxidants released by:

  • Macrophages
  • SMCs
  • Endothelial cells

BIOM30001 - Frontiers in Biomedicine (35 decks)

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