S4) Lipid Transport

Question 1

Lipids are a structurally diverse group of compounds.

Categorise lipids

Answer 1

Question 2

Lipids are hydrophobic molecules, hence insoluble in water.

How are they transported in light of this?

Answer 2

Lipids are transported in blood bound to carriers

Question 3

How are different types of lipids transported in the blood?

Answer 3

• ~ 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

Question 4

Describe the structure of a phospholipid molecule

Answer 4

Question 5

Where are phospholipid molecules seen?

Answer 5

Question 6

Describe the formation and function of cholesterol

Answer 6

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

Question 7

Cholesterol also acts as a precursor for several molecules.

Identify some

Answer 7

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

Question 8

How is cholesterol transported?

Answer 8

Transported around body as cholesterol ester

Question 9

Describe the structure of a lipoprotein molecule

Answer 9

Question 10

What are the contents of a lipoprotein molecule?

Answer 10

Question 11

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

Answer 11

Question 12

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

Identify them

Answer 12

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

Question 13

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

Answer 13

Question 14

Lipoprotein density is obtained by flotation ultracentrifugation.

What is the observed relationship between density and diameter?

Answer 14

Particle diameter is inversely proportional to density

Question 15

Rank the different lipoprotein molecules according to their density and diameter

Answer 15

Question 16

What is the relationship between lipoproteins and apolipoproteins?

Answer 16

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

Question 17

Which two apolipoproteins are of clinical significance?

Answer 17

• apoB (VLDL, IDL, LDL)
• apoAI (HDL)

Question 18

Identify the two roles of apolipoproteins

Answer 18

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

Question 19

In 8 steps, outline chylomicron metabolism

Answer 19

⇒ 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

Question 20

What are chylomicron remnants?

Answer 20

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

Question 21

What is lipoprotein lipase and where is it found?

Answer 21

• 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

Question 22

In 5 steps, outline VLDL metabolism

Answer 22

⇒ 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)

Question 23

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

Answer 23

⇒ 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

Question 24

Illustrate the relationship between VLDL, IDL and LDL metabolism

Answer 24

Question 25

Describe the structure and function of the LDL particle

Answer 25

- **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)

Question 26

The IDL particle is short lived in comparison to the LDL particle. What is the clinical relevance of this?

Answer 26

- **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**

Question 27

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

Answer 27

⇒ 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

Question 28

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

Answer 28

LDL receptor expression controlled by **cholesterol concentration** in cell

Question 29

Describe the three possible pathways for the synthesis of HDL

Answer 29

- 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

Question 30

How do HDL particles mature?

Answer 30

- Nascent HDL **accumulates phospholipids and cholesterol** from cells lining blood vessels - Hollow core progressively fills and particle takes on more globular shape

Question 31

Explain the role of HDL in reverse cholesterol transport

Answer 31

- 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**

Question 32

What is the clinical relevance of reverse cholesterol transport?

Answer 32

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

Question 33

What is the fate of mature HDL particles?

Answer 33

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

Question 34

Describe the role of HDL in cholesterol transfer

Answer 34

- 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)

Question 35

Illustrate a summary of HDL metabolism in terms of the following: - Formation - Maturation - Reverse cholesterol transport - Cholesterol transfer - Breakdown

Answer 35

Question 36

What are hyperlipoproteinaemias?

Answer 36

- **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

Question 37

What is hypercholesterolaemia?

Answer 37

- **Hypercholesterolaemia** is a condition where there is a high level of cholesterol in blood - It presents with cholesterol deposits in various areas of body

Question 38

Identify and describe the three clinical signs of hypercholesterolaemia

Answer 38

- **Xanthelasma** – yellow patches on eyelids - **Tendon xanthoma** – nodules on tendon - **Corneal arcus** – obvious white circle around eye (common in older people)

Question 39

Raised serum LDL is associated with atherosclerosis. Outline the pathway in which oxidised LDL leads to angina, myocardial infarction or stroke due to atherosclerosis

Answer 39

Question 40

Illustrate the different stages between plaque formation and plaque rupture

Answer 40

Question 41

The first approach of treating hyperlipoproteinaemias is conservative. Describe the conservative treatment of this condition

Answer 41

- **Diet** – reduce cholesterol and saturated lipids in diet and increase fibre intake - **Lifestyle** – increase exercise and stop smoking to reduce cardiovascular risk

Question 42

The first approach of treating hyperlipoproteinaemias is specific. Describe the pharmacological treatment of this condition

Answer 42

- **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

Question 43

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

Answer 43

Question 44

Identify and describe the 6 different cholesterol tests available

Answer 44

- **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