Chemical Pathology: Lipoprotein metabolism, Cardiovascular disease and Obesity

Question 1

Name the plasma lipoproteins, in order of increasing density/ decreasing size.

Answer 1

Chylomicrons > VLDL > LDL > HDL

Question 2

Which plasma lipoprotein is predominantly associated with transport of cholesterol?

Answer 2

LDL (~70%)

Question 3

Which plasma lipoprotein is predominantly associated with transport of triglycerides?

Answer 3

VLDL (~55%)

Question 4

What is NPC1L1?

Answer 4

A transmembrane protein that transports cholesterol from the small intestine to the liver (Via lymphatics)

Question 5

Outline the synthesis of cholesterol

Answer 5

• Occurs in the liver
• Acetate is converted to Mevalonic acid (MVA), which is converted to cholesterol (By HMG CoA reductase)
• Is down-regulated with increased absorption of cholesterol

Question 6

What are ABC G5 and ABC G8?

Answer 6

-Transmembrane proteins involved in transport of cholesterol from liver into small intestine

Question 7

How is cholesterol absorption regulated?

Answer 7

• NPC1L1 facilitates cholesterol absorption from small intestine into the liver.
• ABC G5 and ABC G8 transport cholesterol back into small intestine.

Question 8

Outline the metabolism of cholesterol

Answer 8

• 2 main pathways:
  1: Hydrolysed intro bile acids (by 7-α-hydroxylase)
  2: Esterified into cholesterol esters (By ACAT)
• Encorporated into VLDL (along with apoB and triglycerides)
• MTP transfers VLDL from liver into plasma.
• VLDL can be converted into LDL which is taken up by cells with LDL receptors (Mainly peripheries)

Question 9

What is the function of MTP?

Answer 9

• Microsomal Triglyceride transfer Protein
• Transports newly formed VLDL from liver into plasma

Question 10

What is the function of apoB?

Answer 10

• Apolipoprotein B
• The main protein constituent of lipoproteins
• Encorporated into VLDL with cholesterol and triglycerides

Question 11

What is the function of ACAT?

Answer 11

• Sterol O-acyltransferase
• Converts cholesterol into cholesterol esters.

Question 12

What is the main function of LDL?

Answer 12

-Transports cholesterol from the liver to the peripheries, where it is taken up by cells with LDL receptors.

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(ie transports cholesterol to peripheries)

Question 13

What is the main function of HDL?

Answer 13

-Picks up excess cholesterol from the peripheries into the liver.

Question 14

What is the function of ABC A1?

Answer 14

-ABC A1 mediates the movement of free cholesterol from peripheral cells to HDL

Question 15

What is the function of CETP?

Answer 15

• Cholesterol Ester Transfer Protein
• Mediates the movement of cholesterol esters from HDL into VLDL, and the movement of triglycerides from VLDL to HDL

Question 16

What is the function of SR-B1?

Answer 16

-Absorbs HDL from the plasma into the liver

Question 17

Describe how cholesterol crystals form in atherosclerosis

Answer 17

• Excess LDL is oxidised and taken up by macrophages
• Cholesterol is esterified, leading to formation of foam cells.
• Foam cells die, releasing cholesterol
• Cholesterol crystals form in necrotic core

Question 18

Outline triglyceride transport and metabolism

Answer 18

• Absorbed in the small intestine, chylomicrons are formed in the plasma
• Chylomicrons are hydrolysed (By LPL: Lipoproteinlipase, in capillaries) into free fatty acids
• Fatty acids are taken up by the liver and adipose tissue.
• Liver resynthesises triglycerides from fatty acids
• Triglycerides are exported by VLDL
• Triglycerides cyclically hydrolysed into free fatty acids by LPL.

Question 19

Clinical features of familial hypercholesterolaemia?

Answer 19

• Xanthalasma: Eye lumps
• Homozygous: high cholesterol in childhood. Arcus of cholesterol around the iris of the eye.
• Heterozygous: High cholesterol in early adulthood
• High cholesterol on bloods, of course
• Xanthoma: lump on back of achilles tendon
• Eruptive xanthoma: red papules

Question 20

Outline the causes of hyperlipidaemia

Answer 20

• Primary hypercholesterolaemia: eg familial, LDL receptor mutation.
• Primary hypertriglyceridaemia: eg familial type I, lipoprotein lipase deficiency.
• Primary mixed hyperlipidaemia: eg familial, dys-β-lipoproteinaemia (type III). ApoE polymorphism: yellow palmer crease.
• Secondary hyperlipidaemia: eg hypothyroidism

Question 21

Oultine the causes of hypolipidaemia

Answer 21

• A-β-lipoproteinaemia: MTP deficiency (Microsomal triglyceride transfer protein)(recessive).
• Hypo-β-lipoproteinaemia: truncated apoB (dominant)
• Tangier disease: ABC A1 mutation leading to HDL deficiency.

Question 22

Describe the relationship between lipids and cardiovascular disease

Answer 22

• Raised serum cholesterol is associated with increased incidence of cardiovascular disease.
• Increased LDL is also associated
• Decreased HDL is also associated

Question 23

Describe current lipid-lowering therapy

Answer 23

• Statins (eg atorvastatin) are mainstay treatment. Reduces LDL by up to 50%. Reduce CVD mortality.
• Gemfibrozil: reduces triglycerides
• Ezetimibe: cholesterol absorption blocker (inhibits NPC1L1) -
• Colestyramine: binds bile acids, preventing reabsorption.

Question 24

Outline the treatment for obesity

Answer 24

• Hypocaloric diet and excercise
• Orlistat: prevents absorption of fat
• Bariatric surgery: if BMI >40 (eg gastric band)

Question 25

Outline the causes of Secondary hyperlipidaemia

Answer 25

• Hormonal: Pregnancy, exogenous hormones, hypothyroidism
• Metabolic: Diabetes, gout, obesity
• Renal dysfunction: Nephrotic syndrome, CKD
• Obstructive liver disease
• Toxins: eg alcohol.
• Iatrogenic: eg antihypertensives

Question 26

Give one cause of primary hypercholesterolaemia

Answer 26

-Familial, LDL receptor mutation.

Question 27

Give one cause of primary hypertriglyceridaemia

Answer 27

-Familial type I, lipoprotein lipase deficiency.

Question 28

Give one cause of primary mixed hyperlipidaemia

Answer 28

-Familial, dys-β-lipoproteinaemia (type III). ApoE polymorphism: yellow palmer crease.