S4) Lipid Transport Flashcards Preview

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Flashcards in S4) Lipid Transport Deck (44)
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1
Q

Lipids are a structurally diverse group of compounds.

Categorise lipids

A
2
Q

Lipids are hydrophobic molecules, hence insoluble in water.

How are they transported in light of this?

A

Lipids are transported in blood bound to carriers

3
Q

How are different types of lipids transported in the blood?

A
  • ~ 2% of lipids (fatty acids) are carried bound to albumin (limited capacity)
  • ~ 98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins & TAG
4
Q

Describe the structure of a phospholipid molecule

A
5
Q

Where are phospholipid molecules seen?

A
6
Q

Describe the formation and function of cholesterol

A
  • Formation: some obtained from diet, but most synthesised in liver
  • Function: essential component of membranes (modulates fluidity)
7
Q

Cholesterol also acts as a precursor for several molecules.

Identify some

A
  • Precursor of steroid hormones e.g. cortisol, aldosterone, testosterone
  • Precursor of bile acids
8
Q

How is cholesterol transported?

A

Transported around body as cholesterol ester

9
Q

Describe the structure of a lipoprotein molecule

A
10
Q

What are the contents of a lipoprotein molecule?

A
11
Q

What are the two types of apolipoproteins found on a lipoprotein molecule?

A
12
Q

There are five distinct classes of lipoproteins named according to density.

Identify them

A
  • Chylomicrons
  • VLDL (very low density lipoproteins)
  • IDL (intermediate density lipoproteins)
  • LDL (low density lipoproteins)
  • HDL (high density lipoproteins)
13
Q

Illustrate how each type of lipoprotein contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester

A
14
Q

Lipoprotein density is obtained by flotation ultracentrifugation.

What is the observed relationship between density and diameter?

A

Particle diameter is inversely proportional to density

15
Q

Rank the different lipoprotein molecules according to their density and diameter

A
16
Q

What is the relationship between lipoproteins and apolipoproteins?

A

Each class of lipoprotein particle has a particular complement of associated proteins (apolipoproteins)

17
Q

Which two apolipoproteins are of clinical significance?

A
  • apoB (VLDL, IDL, LDL)
  • apoAI (HDL)
18
Q

Identify the two roles of apolipoproteins

A
  • Structural: packaging water insoluble lipid
  • Functional: co-factor for enzymes and ligands for cell surface receptors
19
Q

In 8 steps, outline chylomicron metabolism

A

⇒ In small intestine, apoB-48 added to chylomicrons before entering lymph

⇒ Travel to thoracic duct & empties into left subclavian vein

⇒ Acquire 2 new apoproteins (apoC and apoE) once in blood

⇒ apoC binds lipoprotein lipase on adipocytes and muscle

⇒ Released FA enter cells depleting fat content in chylomicron

Chylomicron remnants return to liver

LDL receptor on hepatocytes binds apoE, chylomicron remnant taken up by receptor mediated endocytosis

Lysosomes release remaining contents for metabolic use

20
Q

What are chylomicron remnants?

A

Chylomicron remnants are molecules formed when triglyceride content is reduced to ~20% and apoC dissociates

21
Q

What is lipoprotein lipase and where is it found?

A
  • LPL is an enzyme that hydrolyses TAG in lipoproteins and requires ApoC-II as cofactor
  • It is found attached to surface of endothelial cells in capillaries
22
Q

In 5 steps, outline VLDL metabolism

A

⇒ In liver, apoB100 added during formation

apoC and apoE added from HDL particles in blood

⇒ VLDL binds to LPL on endothelial cells in muscle and adipose

⇒ TAG content depletes

⇒ Released FA used for energy production (muscle) / re-synthesis of TAG and fat storage (adipose)

23
Q

In four steps, explain how IDL and LDL are formed from VLDL

A

⇒ VLDL particles dissociate from LPL as TAG content depletes and return to liver

IDL particle is formed if VLDL content depletes to ~30% (short lived)

⇒ IDL particles can return to liver / rebind to LPL enzyme to further deplete TAG content

LDL particle is formed if depletion to ~ 10% as IDL loses apoC & apoE

24
Q

Illustrate the relationship between VLDL, IDL and LDL metabolism

A
25
Q

Describe the structure and function of the LDL particle

A
  • Structure: do not have apoC or apoE, hence aren’t efficiently cleared by liver (liver LDL-Receptor has a high affinity for apoE)
  • Function: provide cholesterol from liver to peripheral tissues (peripheral cells LDL receptor takes up LDL via receptor mediated endocytosis)
26
Q

The IDL particle is short lived in comparison to the LDL particle.

What is the clinical relevance of this?

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
27
Q

In four steps, describe how LDL enters peripheral cells by receptor mediated endocytosis

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

28
Q

What controls the receptor-mediated endocytosis of LDL in peripheral cells?

A

LDL receptor expression controlled by cholesterol concentration in cell

29
Q

Describe the three possible pathways for the synthesis of HDL

A
  • Synthesised by liver and intestine (low TAG levels)
  • Bud off from chylomicrons and VLDL as they are digested by LPL
  • Free apoA-I acquires cholesterol and phospholipid from other lipoproteins and cell membranes
30
Q

How do HDL particles mature?

A
  • Nascent HDL accumulates phospholipids and cholesterol from cells lining blood vessels
  • Hollow core progressively fills and particle takes on more globular shape
31
Q

Explain the role of HDL in reverse cholesterol transport

A
  • HDL remove cholesterol from cholesterol-laden cells and return it to liver
  • ABCA1 protein within cell facilitates transfer of cholesterol to HDL
  • Cholesterol then converted to cholesterol ester by LCAT
32
Q

What is the clinical relevance of reverse cholesterol transport?

A

Reduces likelihood of foam cell and atherosclerotic plaque formation in blood vessels

33
Q

What is the fate of mature HDL particles?

A

Mature HDL taken up by liver via specific receptors and degraded by lysosomes

34
Q

Describe the role of HDL in cholesterol transfer

A
  • 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)
35
Q

Illustrate a summary of HDL metabolism in terms of the following:

  • Formation
  • Maturation
  • Reverse cholesterol transport
  • Cholesterol transfer
  • Breakdown
A
36
Q

What are hyperlipoproteinaemias?

A
  • Hyperlipoproteinaemias are conditions causing a raised plasma level of 1/more lipoprotein classes as a result of over-production or under-removal
  • This occurs due to defects in enzymes, receptors or apolipoproteins
37
Q

What is hypercholesterolaemia?

A
  • Hypercholesterolaemia is a condition where there is a high level of cholesterol in blood
  • It presents with cholesterol deposits in various areas of body
38
Q

Identify and describe the three clinical signs of hypercholesterolaemia

A
  • Xanthelasma – yellow patches on eyelids
  • Tendon xanthoma – nodules on tendon
  • Corneal arcus – obvious white circle around eye (common in older people)
39
Q

Raised serum LDL is associated with atherosclerosis.

Outline the pathway in which oxidised LDL leads to angina, myocardial infarction or stroke due to atherosclerosis

A
40
Q

Illustrate the different stages between plaque formation and plaque rupture

A
41
Q

The first approach of treating hyperlipoproteinaemias is conservative.

Describe the conservative treatment of this condition

A
  • Diet – reduce cholesterol and saturated lipids in diet and increase fibre intake
  • Lifestyle – increase exercise and stop smoking to reduce cardiovascular risk
42
Q

The first approach of treating hyperlipoproteinaemias is specific.

Describe the pharmacological treatment of this condition

A
  • Statins – reduce cholesterol synthesis by inhibiting HMG-CoA reductase
  • Bile salt sequestrants – bind bile salts in GI tract and forces liver to produce more bile acids using more cholesterol
43
Q

Describe the method of action of statin drugs in the pharmacological treatment of hyperlipoproteinaemias

A
44
Q

Identify and describe the 6 different cholesterol tests available

A
  • Total Cholesterol – ideally 5 mmol/L or less
  • Non HDL-Cholesterol – ideally 4mmol/L or less
  • LDL-Cholesterol – ideally 3 mmol/L or less
  • HDL-Cholesterol – ideally over 1-1.2mmol/L (men&women)
  • Total cholesterol:HDL-C ratio – ratio > 6 considered high risk
  • Triglyceride – ideally < 2mmol/L in fasted sample