ChemPath: Lipoprotein metabolism, CVD and obesity

Question 1

What are the features of an atherosclerotic lesion?

Answer 1

• Fibrous cap
• Foam cells (macrophages full of cholesteryl ester/ox-LDL)
• Necrotic core (full of cholesterol crystals)

Question 2

What is the biggest plasma lipoprotein?

Answer 2

Chylomicrons

Question 3

During what time will chylomicrons be most abundant?

Answer 3

After eating (they are present in very small amounts in the fasted state)

Question 4

Describe the uptake of cholesterol by the intestinal epithelium.

Answer 4

• Cholesterol entering the intestines will come from the diet and bile
• Cholesterol will be solubilised in mixed micelles
• It is then transported cross the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)

Question 5

Name two transports that transport cholesterol back into the intestinal lumen.

Answer 5

ABC G5
ABC G8

Transports back to lumen, promoting elimination
(opposite action of NPC1L1)

Question 6

Where are bile acids absorbed?

Answer 6

Terminal ileum

Question 7

What happens when cholesterol arrives at the liver?

Answer 7

Downregulates the activity of HMG CoA reductase

NOTE: HMG CoA reductase is responsible for the production of cholesterol from acetate and mevalonic acid

Question 8

What are the two fates of cholesterol that is either produced by or transported to the liver?

Answer 8

• Hydroxylation by 7a-hydroxylase to produce bile acids
• Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerids and ApoB

Question 9

Which transfer protein is important in the packaging of VLDLs?

Answer 9

MTP (Microsomal triglyceride transfer protein)

*lomitapide is an MTP inhibitor

*Packaging HDLs -> ABCA1
Packaging LDLs -> MTP

Question 10

Which transfer protein is important in the packaging of HDLs?

Answer 10

ABCA1

*Packaging HDLs -> ABCA1
Packaging LDLs -> MTP

Packaging HDLs -> ABCA1
Packaging LDLs -> MTP

Question 11

What are the effects of CETP on the movement of substances between lipoproteins?

Answer 11

• Moves cholesterol from HDL → VLDL
• Moves triglycerids from VLDL → HDL

Question 12

Which receptor is responsible for the uptake of some HDLs by the liver?

Answer 12

SR-B1

Question 13

Describe the transport and metabolism of triglycerides.

Answer 13

• Triglycerides are hydrolysed into FFAs + glycerol (by the action of lipoprotein lipase), absorbed, then resynthesized into triglycerides
• Transported in the plasma by: chylomicrons & VLDLs
• Some FFAs are taken up by the liver, and some by adipose tissue
• The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs to be transported

Question 14

List the three causes of familial hypercholesterolaemia (type II).

Answer 14

• Caused by autosomal dominant gene mutations in:
  
  • LDL receptor
  • ApoB
  • PCSK9

Question 15

List some mutations that are implicated in polygenic hypercholesterolaemia.

Answer 15

• NPC1L1
• HMGCR
• CYP7A1

Question 16

What is familial hyperalphalipoproteinaemia?

Answer 16

• Increase in HDL caused by deficiency of CETP
• This is associated with longevity

Question 17

What is phytosterolaemia?

Answer 17

*Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8
Meaning prevention of transporting cholesterol into intestinal lumen for elimination
Hence this condition is associated with premature atherosclerosis

Question 18

Dsecribe the function of the LDL receptor.

Answer 18

• LDLs bind to LDLR in coated pits which then undergo endocytosis (thereby uptaking the LDL into the liver)

Question 19

List some clinical features of familial hypercholesterolaemia.

Answer 19

• Xanthelasma
• Corneal arcus
• Tendon xanthomata
• Atherosclerosis affecting coronary arteries and root of aorta
• In some cases, death <20 years

Question 20

What is PCSK9?

Answer 20

• A protein that binds to LDL receptors and degrades them

NOTE: gain of function mutations result in increased breakdown of LDLR and hence increased plasma LDL levels

Question 21

List the key features of the following forms of primary hypertriglyceridaemia:

• Familial Type I
• Familial Type IV
• Familial Type V

Answer 21

Familial Type I:

• Caused by deficiency of lipoprotein lipase (hence can’t hydrolyse TGs) and ApoC II
• NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase

Familial Type IV:

• Characterised by increased synthesis of triglycerides

Familial Type V:

• Characterised by deficiency of ApoA V
• NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate

Question 22

What is familial combined hyperlipidaemia?

Answer 22

Some people in the family have high cholesterol and others have high triglycerides

Question 23

What is familial dysbetalipoproteinaemia (type III)?

Answer 23

• Polymorphism of ApoE
• Specifically, due to aberrant form of ApoE (E2/2) (normal form is ApoE (3/3))
• A diagnostic clinical feature of yellowing of the palmar crease (palmar striae)

Question 24

List some causes of secondary hyperlipidaemia.

Answer 24

• Pregnancy
• Hypothyroidism
• Obesity
• Nephrotic syndrome

Question 25

List four causes of hypolipiademia and their underlying genetic defect.

Answer 25

**Aβ-lipoproteinaemia:** * Autosomal recessive * Extremely low levels of cholesterol * Due to deficiency of MTP **Hypoα-lipoproteinaemia:** * Sometimes caused by mutation of ApoA1 **Hypoβ-lipoproteinaemia:** * Autosomal dominant * Low LDL * Caused by mutations in ApoB **Tangier disease:** * Low HDL * Caused by mutation of ABCA1

Question 26

Describe the role of LDL in atherosclerosis.

Answer 26

* LDL becomes oxidised once it has got through the vascular endothelium = oxLDL * oxLDL gets esterified & phagocytosed by macrophages, becoming foam cells

Question 27

List some lipid-lowering drugs and their effect on lipid levels (4).

Answer 27

* **Statins** - ↓ LDLs, ↑ HDLs, slight increased in triglycerides * **Nicotinic acid** - lipoprotein(a) levels, ↑HDL, ↓TG, ↓LDL **Ezetimibe** - inhibits NPC1L1 receptor, thus inhibiting cholesterol uptake in SI * **Colestyramine** - resin that binds to bile acids and reduces their absorption

Question 28

List some novel forms of lipid-lowering drugs.

Answer 28

* **Lomitapide** - MTP blocker * **REGN727 (evolucumab, alirocumab)** - anti-PCSK9 monoclonal antibody * **Mipomeren** - anti-sense ApoB oligonucleotide

Question 29

List three types of bariatric surgery.

Answer 29

* Gastric banding * Roux-en-Y gastric bypass * Biliopancreatic diversion

Question 30

What is the definition of success in bariatric surgery?

Answer 30

More than 50% reduction in excess weight

Question 31

List some beneficial effects of bariatric surgery.

Answer 31

* Reduced diabetes risk * Reduced serum triglycerides * Increased HDLs * Reduced fatty liver * Reduced blood pressure

Question 32

Indications for bariatric surgery

Answer 32

Indicated if BMI >40, or >35 + comorbidity

Question 33

Outline management for obesity

Answer 33

Conservative (diet + wt loss) Medical: orlistat - profound flatulence & diarrhoea, so poor adherence Surgical: bariatric surgery - 3 types - gastric sleeve, roux en y, biliopancreatic diversion

Question 34

What is rimonabant, why was it discontinued

Answer 34

Medical tx for obesity Cannabinoid antagonist Discont due to inc risk of suicide

Question 35

Rate-limiting step in cholesterol synthesis, also a target for statins?

Answer 35

HMG CoA reductase

Question 36

Function of lipoproteins?

Answer 36

Carry triglycerides and cholesterol

Question 37

Name the lipoproteins, in order of lowest to highest density

Answer 37

Chylomicron (high triglyceride content, and high after eating) VLDL LDL IDL HDL