Chem Path 2 - Lipid metabolism

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

What is the biggest plasma lipoprotein?

Answer 2

Chylomicrons

Question 3

During what time will chylomicrons be most abundant?

Answer 3

After eating

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 across 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

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 ApoB

Question 9

Which transfer protein is important in the packaging of VLDLs?

Answer 9

MTP

Question 10

Which transfer protein is important in the packaging of HDLs?

Answer 10

ABC A1

Question 11

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

Answer 11

Moves cholesterol from HDL to VLDL

Moves triglycerides from VLDL to 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 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 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

NOTE: this condition is associated with premature atherosclerosis

Question 18

Describe 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

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 Familial Type I hypertriglyceridaemia

Answer 21

Caused by deficiency of lipoprotein lipase and ApoC II

NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase

Question 22

List the key features of Familial Type IV hypertriglyceridaemia

Answer 22

Characterised by increased synthesis of triglycerides

Question 23

List the key features of Familial Type V hypertriglyceridaemia

Answer 23

Characterised by deficiency of ApoA V

Question 24

What is familial combined hyperlipidaemia?

Answer 24

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

Question 25

What is familial dysbetalipoproteinaemia (type III)?

Answer 25

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)

Question 26

List some causes of secondary hyperlipidaemia.

Answer 26

Pregnancy

Hypothyroidism

Obesity

Nephrotic syndrome

Question 27

List four causes of hypolipidaemia and their underlying genetic defect.

Answer 27

Ab-lipoproteinaemia

· Autosomal recessive

· Extremely low levels of cholesterol

· Due to deficiency of MTP

Hypob-lipoproteinaemia

· Autosomal dominant

· Low LDL

· Caused by mutations in ApoB

Tangier disease

· Low HDL

· Caused by mutation of ABC A1

Hypoa-lipoproteinaemia

· Sometimes caused by mutation of ApoA1

Question 28

Describe the role of LDL in atherosclerosis.

Answer 28

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 29

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

Answer 29

Statins – reduce LDLs, increase HDLs, slight increase in triglycerides

Fibrates – lower triglycerides, little effects on LDL/HDL

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

Mipomersen – anti-sense ApoB oligonucleotide

Question 31

List three types of bariatric surgery.

Answer 31

Gastric banding

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

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