Chemical Pathology 2 - Lipoprotein metabolism, CVD and obesity

Question 1

What is the role of HDL?

Answer 1

Picks up excess cholesterol from the periphery and transports it to liver

Question 2

Describe the uptake of cholesterol by the intestinal epithelium.

Answer 2

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 3

What is the main component of mixed micelles?

Answer 3

Bile acids

Question 4

Where are bile acids reabsorbed?

Answer 4

Terminal ileum

Question 5

What controls the amount of cholesterol reabsorbed into the intestine?

Answer 5

Balance of 2 enzymes: NPC1L1 (transports cholesterol OUT of the intestinal lumen) and ABC G5/G8 (transports cholesterol back INTO the intestinal lumen)

ABC = ATP-binding casette transporter

Question 6

What is the key enzyme involved in cholesterol synthesis?

Answer 6

HMG CoA reductase

Question 7

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

Answer 7

Hydroxylation by 7 alpha-hydroxylase to produce bile acids

Esterification by ACAT to produce cholesteryl ester which is incorporated into VLDLs along with triglycerides and ApoB

*ACAT: Acyl-CoA cholesterol acyltransferase*

Question 8

Which transfer protein is important in the packaging of VLDLs?

Answer 8

MTP (microsomal triglyceride transfer protein)

Question 9

Which transfer protein is important in the packaging of HDLs?

Answer 9

ABC A1

Question 10

What is the role of CETP in cholesterol metabolism?

Answer 10

Cholesterol Ester Transfer Protein:

Mediates the movement of cholesterol from HDL to VLDL

Mediates the movement of triglycerides from VLDL to HDL

Question 11

Which receptor enables the uptake of HDL by the liver?

Answer 11

SR-B1

Question 12

Which enzyme converts cholesterol to cholesteryl ester?

Answer 12

ACAT

Question 13

What is VLDL constituted of?

Answer 13

ApoB, cholesteryl ester and triglyceride

Question 14

What is the function of 7-alpha hydroxase in cholesterol metabolism?

Answer 14

Converts cholesterol to bile acids

Question 15

Describe the transport and metabolism of triglycerides.

Answer 15

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 16

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

Answer 16

Caused by autosomal dominant gene mutations in:

LDL receptor

ApoB

PCSK9 (Proprotein convertase subtilisin/kexin type 9)

*Patients are most commonly heterozygous - homozygous dominant presents with more extreme symptoms*

Question 17

Which mutations are implicated in polygenic hypercholesterolaemia?

Answer 17

NPC1L1, HMG-CoA reductase, CYP7A1 polymorphisms

Question 18

What name is given to an inherited predeliction to high HDL, and what mutation causes this?

Answer 18

Familial hyper alpha lipoproteinaemia = CETP deficiency

Question 19

What condition is caused by ABC G5/G8 mutation?

Answer 19

Phytosterolaemia

Question 20

What is phytosterolaemia?

Answer 20

Inherited condition that allows plant sterols to enter the plasma freely, which are more athrogenic than cholesterol itself

Leads to premature atherosclerosis

Question 21

Recall 3 clinical signs of hypercholesterolaemia

Answer 21

Xanthalasma

Arcus

Tendon xanthoma

Question 22

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

a. Familial Type I
b. Familial Type IV
c. Familial Type V

Answer 22

a. 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
b. Familial Type IV Characterised by increased synthesis of triglycerides
c. Familial Type V Characterised by deficiency of ApoA V

NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate

Question 23

What are the primary causes of mixed hyperlipidaemia?

Answer 23

Familial combined hyperlipidaemia (unknown cause)

Familial hepatic lipase deficiency

Familial dysbetalipoproteinaemia (type III hyperlipoproteinaemia) due to an ApoE2 polymorphism -> yellow palmar crease is a diagnostic sign

*Examples of secondary causes of mixed hyperlipidaemia include PBC*

Question 24

Recall 3 inherited conditions that can cause hypolipidaemia

Answer 24

A-beta-lipoproteinaemia (MTP deficiency, autosomal recessive, rare)

Hypo-beta-lipoproteinaemia (truncated ApoB, autosomal dominant)

Tangier disease/hypo-alpha-lipoproteinaemia (HDL deficiency caused by ABC A1 mutations)

*There are other forms of hypo-alpha-lipoproteinaemia which can be caused by ApoA1 mutations*

Question 25

What is the effect of statins on cholesterol levels?

Answer 25

Very effective at reducing LDL, also reduce triglyceride and increase HDL

Question 26

What is the effect of fibrate drugs on cholesterol levels?

Answer 26

Very effective at reducing triglycerides, also reduces LDL

Question 27

What is the role of PCSK9?

Answer 27

Binds LDLR and promotes its degradation. Inhibiting PCSK9 with monoclonal antibodies reduces blood LDL.

*Rare cause of FH is a gain-of-function mutation in PCKS9 -> leads to increased LDLR degradation so the liver can’t take up as much LDL*

Question 28

What is the mechanism of action of statins?

Answer 28

HMG coA reductase inhibition

Question 29

Cholesterol absorption, metabolism and transport

Answer 29

Question 30

Triglyceride absorption, metabolism and transport

Answer 30