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)
• Necrotic core (full of cholesterol crystals)

Question 2

Types of plasma lipoproteins:

Answer 2

• Chylomicrons - LARGEST
• VLDL - rich in triglycerides
• LDL - main carriers of cholesterol
• HDL

Question 3

During what time will chylomicrons be most abundant?

Answer 3

Levels peak after eating (they are present in very small amounts in the fasted state as they have a short half-life)

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 transporters that transport cholesterol back into the intestinal lumen.

Answer 5

ABC G5

ABC G8

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 triglycerides and Apo(B)

Question 9

What is the main precursor of LDL?

Answer 9

VLDL

LDL circulates around body for ≈3 days, then gets taken by via LDL receptor on liver

Question 10

How do LDL and HDL differ in their transport?

Answer 10

LDL: distributing cholesterol from liver to the peripheries
HDL: taking excess cholesterol from peripheries back to the liver, using transfer protein ABCA1

Question 11

Which transfer protein is important in the packaging of VLDLs?

Answer 11

MTP

Question 12

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

Answer 12

• Moves cholesterol from HDL → VLDL
• Moves triglycerides from VLDL → HDL

Question 13

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

Answer 13

SR-B1

Question 14

Describe the transport and metabolism of triglycerides.

Answer 14

• Main source of triglycerides = from fatty food diet (absorbed in the small intestine)
• Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma
• Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids
• Some free fatty acids are taken up by the liver, and some by adipose tissue
• The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs
• VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids

Question 15

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

Answer 15

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

Question 16

List some mutations that are implicated in polygenic hypercholesterolaemia.

Answer 16

Multiple loci that lead to modest increase in cholesterol

• NPC1L1
• HMGCR
• CYP7A1

Question 17

What is familial hyperalphalipoproteinaemia?

Answer 17

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

Question 18

What is phytosterolaemia?

Answer 18

Photo meaning ‘plant’…

• Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8 (the cholesterol transporters in the small intestine)

NOTE: this condition is associated with premature atherosclerosis as plant sterols can enter the bloodstream freely

Question 19

Dsecribe the function of the LDL receptor.

Answer 19

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

Question 20

List some clinical features of familial hypercholesterolaemia.

Answer 20

• Xanthelasma
• Corneal arcus
• Tendon xanthomata –> feel achilles tendon for thickness!
• Cholesterol levels extremely high (>30 mmol/L from birth)

Question 21

What is PCSK9?

Answer 21

• 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

NOTE: loss of function mutations are associated with lower LDL levels*

Question 22

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

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

Answer 22

Familial Type I:

• Caused by deficiency of lipoprotein lipase 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 e.g. may show chylomicrons, VLDLs etc. depending on the type of hyperlipidaemia

Question 23

What is familial combined hyperlipidaemia?

Answer 23

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

Unknown cause typically

Question 24

What is familial dysbetalipoproteinaemia (type III)?

Answer 24

UNCOMMON
* Due to aberrant form of ApoE (E2/2)
* NOTE: normal form is ApoE (3/3)
* A diagnostic clinical feature of yellowing of the palmar crease (palmar striae) AND may also have irruptive xanthoma on the elbow

Question 25

List some causes of secondary hyperlipidaemia.

Answer 25

* Pregnancy * Exogenous sex-hormones * Hypothyroidism * Obesity * Nephrotic syndrome (switches on VLDL and LDL synthesis)

Question 26

List four causes of hypolipiademia and their underlying genetic defect.

Answer 26

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

Question 27

Describe the role of LDL in atherosclerosis.

Answer 27

* LDL becomes oxidised once it has got through the vascular endothelium * Once oxidised it is taken up by macrophages * Within the macrophages, the LDLs become esterified and you develop foam cells

Question 28

What can cause a thrombus?

Answer 28

Thin fibrous cap surrounding cholesterol --> ruptures e.g. from strain Once cap ruptures, cholesterol is exposed, forming a thrombus THEN, cap can either heal (progress of occlusion) OR cholesterol thrombus completely occludes the vessel

Question 29

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

Answer 29

* **Statins** - reduce LDLs, increased HDLs, slight increased in triglycerides * **Fibrates e.g. gemfibrozil** - lower triglycerides, little effects * **Ezetimibe** - reduces cholesterol absorption (blocks NPC1L1) * **Colestyramine** - resin that binds to bile acids and reduces their absorption

Question 30

List some novel forms of lipid-lowering drugs.

Answer 30

* **Lomitapide** - MTP blocker * **REGN727** - anti-PCSK9 monoclonal antibody * **Mipomeren** - anti-sense ApoB oligonucleotide

Question 31

List three types of bariatric surgery.

Answer 31

* Gastric banding --> restricts how much people eat * Roux-en-Y gastric bypass * Biliopancreatic diversion

Question 32

What is the definition of success in bariatric surgery?

Answer 32

More than 50% reduction in excess weight (excess weight = actual - ideal weight)

Question 33

List some beneficial effects of bariatric surgery.

Answer 33

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