Lipoprotein metabolism

Question 1

Lipoproteins smallest to largest

Answer 1

Chylomicrons > VLDL > LDL > HDL (2 types - 2 > 3)

Question 2

Process of cholesterol metabolism

Answer 2

• Dietary cholesterol absorbed across jejenum brush border by NPC1L1 (note ABC G5 + G8 act in opposite direction). More cholesterol is absorbed downstream in the ileum, in the form of bile acids
• Cholesterol goes to liver + down-regulates HMG-coA reductase that synthesises cholesterol de novo
• Either used for bile acid synthesis or esterified by ACAT to form VLDL (LDL pre-cursor)
• LDL can carry cholesterol to the peripheries (bad) or bind LDL receptors on the liver to place cholesterol back in the liver for excretion (better)
• HDL carries cholesterol from peripheries to liver via ABCA1 at periphery + SRB1 at liver
• Cholesterol returned to the liver can be excreted
• CETP transfers cholesterol between LDL + HDL

Question 3

Process of triglyceride metabolism

Answer 3

• Dietary triglyceride absorbed in small intestine + assembled into chylomicrons
• Chylomicrons hydrolysed by LPL enzyme (in skeletal muscle + adipose tissue capillaries) + free fatty acids released into blood
• Free fatty acids used in liver to form VLDL or incorporated into adipose tissue

Question 4

VLDL composition

Answer 4

Cholesterol ester
Triglyceride
ApoB

Question 5

Milky plasma due to excess chylomicrons in blood

Answer 5

LPL deficiency

Question 6

4 types of dyslipidaemia

Answer 6

Hypercholesterolaemia (high cholesterol)
Hypertriglyceridaemia (high triglycerides)
Mixed hyperlipidaemia (high cholesterol + triglycerides)
Hypolipidaemia (low cholesterol + triglyceride)

Question 7

Action of PCSK9 inhibitor

Answer 7

PCSK9 inhibitors lower circulating LDL levels
Circulating LDL is a key risk factor for atherosclerosis
PCSK9 binds and degrades LDL receptors on hepatocytes, which normally helpfully remove LDL from the circulation
PCSK9 inhibitors prevent LDL receptor degradation and reduce circulating LDL levels

Question 8

Main transporters of cholesterol

Answer 8

LDL (70%)

HDL (17%)

Question 9

Main transporters of triglycerides

Answer 9

VLDL

Chylomicrons

Question 10

Two main lipids

Answer 10

Triglyceride

Cholesterol

Question 11

Main carriers of dietary triglyceride absorbed from small intestine

Answer 11

Chylomicrons

Question 12

LDLR (or less commonly apoB / PCSK9 mutations)
Monogenic AD mutation
Reduced LDL absorption = increased circulating LDL only
(Remains circulating for 5d rather than 2d!)
Heterozygosity > homozygosity
Arcus, xanthelasma, tendon xanthoma, pinpoint ostia

Answer 12

Familial hypercholesterolaemia

Question 13

3 types - I (LPL deficiency), III and IV (increased TG synthesis)
= Increased circulating TG only
Monogenic AD mutation
Type I = Milky plasma containing chylomicrons if left overnight
Types III / IV = Milky plasma containing VLDL if left overnight
Episodic abdo pain + recurrent pancreatitis
Eruptive xanthoma

Answer 13

Familial hypertriglyceridaemia

Question 14

Mx familial hypertriglyceridaemia

Answer 14

Depends on cause:
Type I = reduce triglycerides (clearance problem)
Type III/IV = reduce carbohydrates (synthesis problem - reduce carbs to prevent conversion to TG!)

Question 15

Effect of statins

Answer 15

Reduces LDL
Slight increase in HDL
Moderate reduction in TG

Question 16

Novel LDL-lowering therapies

Answer 16

Mimics HDL - very effective at lowering LDL but causes fatty liver
Anti-PCSK9 monoclonal antibody - fortnightly injection, currently most promising