Cholesterol and Lipoprotein Metabolism

Question 1

Which particle(s) contains ApoB-48?

Answer 1

Only chylomicrons. (and chylomicron remnants)

Question 2

Which particle(s) contains ApoB-100?

Answer 2

VLDL, IDL, and LDL

Question 3

Which particle(s) contains ApoE?

Answer 3

VLDL and HDL (and chylomicron remnants)

Question 4

Which particle(s) contains ApoC-II?

Answer 4

Chylomicrons and VLDL

Question 5

What makes the absorption of fats in chylomicrons via lymphatics special compared to the absorption of other nutrients?

Answer 5

These lymphatics bypass the liver, and fat can go straight to adipose for storage.

Question 6

When a chylomicron transitions to a chylomicron remnant, what lipoprotein(s) does it lose/gain?

Answer 6

It loses ApoC-II and picks up ApoE.

Question 7

How is are chylomicron remnants taken up by the liver?

Answer 7

The LDL receptor (LDLR) in hepatocytes binds ApoE on chylomicron remnants.

Question 8

What form of ApoB does this liver make? (and thus, what’s on all the transport particles made by the liver?)

Answer 8

ApoB-100

Question 9

What does LDLR recognize to take up particles?

Answer 9

ApoB-100 and ApoE

Question 10

7 non-genetic (“secondary”) causes of hyperlipoproteinemia?

not a list to memorize, but it shouldn’t surprise you

Answer 10

Diet
Alcohol (-> high TGs)
Insulin resistance / T2DM
Hypothyroidism
Nephrotic syndrome
Chronic renal failure
Meds (lots of them)

Question 11

What’s the mechanism for insulin resistance / T2DM leading to hyperlipoproteinemia?

Answer 11

Because glucose can’t be used, free fatty acids (FFAs) are liberated.
Increased FFA flux to liver leads to increased VLDL production.

Question 12

Which mutations cause Familial Chylomicronemia Syndromes? How? What “Frederickson/Levy” type are these?

Answer 12

Mutatations in ApoC-II or lipoprotein lipase (LPL).
With either missing, TGs can’t be removed from chylomicrons… and they build up.
These are Type I.

Question 13

What skin lesion is associated with Familial Chylomicronemia Syndromes (esp. LPL deficiency)? When will they erupt?

Answer 13

Eruptive xanthomas are associated with lipoprotein lipase deficiency. Eruptions tend to occur after high TG intake.

Question 14

What’s the major clinical issue associated with chylomicrons being too high?

Answer 14

Pancreatitis.

Question 15

What’s the genetic mutation in Familial dysbetalipoproteinemia? (it’s a poor name)
What “type” is this?

Answer 15

ApoE - such that it can’t bind LDLR.

This is Type III.

Question 16

What two processes is ApoE very important in? What do patients with ApoE mutations thus have in their blood?

Answer 16

Chylomicron remnant clearance.
IDL uptake into liver.
Pts without functional ApoE have high levels of “remnants” i.e. chylomicron remnants, and LDL.

Question 17

What skin lesions are associated with ApoE defects / aka dysbetalipoproteinemia / aka Type III hyperlipoproteinemia?

Answer 17

Tuberous xanthomas.

Palmar xanthomas.

Question 18

What clinical problem is associated with ApoE defects?

Answer 18

Increased coronary artery disease (from high LDL).
(Apparently the chylomicron remnants don’t do much harm? - not to be confused with chylomicrons, high levels of which can cause pancreatitis)

Question 19

What’s defective in Familial hypercholesteremia (FH)?

What “type” of hyperlipoproteinemia is this?

Answer 19

LDLR defect (heterozygous is bad, homozygous is worse).
This is Type IIa hyperlipoproteinemia.

Question 20

Which xanthomas are most specifically associated with FH?

Answer 20

Tendon xanthomas - on Achilles’ and tendons of hands.
(corneal arcus and xanthelasma can be present, but are less specific… for example xanthelasma happen in primary billiary sclerosis.)

Question 21

When do you see cutaneous xanthomas?

Answer 21

homozygous FH

Question 22

What do ApoB-100 mutations act just like? Why?

Answer 22

ApoB-100 is the ligand on LDL for LDLR.

Thus, ApoB-100 mutations “phenocopy” FH.

Question 23

What is mutated in autosomal dominant hypercholesterolemia 3 (ADH3)? What hyperlipoproteinemia type is this?

Answer 23

Pcsk9, with a gain of function mutation.

This is also type IIa hyperlipoproteinemia.

Question 24

What effect does a gain of function mutation in Pcsk9 have? Why is this effect dominant?

Answer 24

Pcsk9 targets LDLR for degredation. Too much Pcsk9 activity causes elevated levels of LDL (similar to FH). This is dominant because… it’s a gain of function mutation… one overactive copy of the gene will affect all the LDLRs.

Question 25

What causes familial hypertriglyceridemia? Which hyperlipoproteinemia type is this?

Answer 25

Defects in processing VLDL (removing TGs from the particles.)
This is type IV or V, where V is more severe.

Question 26

But wait. Doesn’t a defect in removing TGs from particles also cause familial hyperchylomicronemia?

Answer 26

Yes, though these are not mutations in LPL. If the defect if bad enough, chylomicron processing is affected, and you get Type V.
Type V = Type I + IV, which is cute.
(he didn’t go into what accounts for the difference in severity. The etiology is unknown.)

Question 27

What is elevated in Familial combined hyperlipidemia? What hyperlipoproteinemia type is this?

Answer 27

VLDL production is increased, but this also leads to elevations in LDL. This is Type IIb.
(the etiology is unknown)

Question 28

What’s the deal with lipoprotein(a) “little a”?

Answer 28

Lp(a) is an independent risk factor for CHD and has levels that are highly genetically determined.
Its function is unknown, though it’s homologous to plasminogen…

Question 29

Why has HDL long been though to be protective against atherosclerotic disease?

Answer 29

It is involved in reverse transport that removes cholesterol from places like macrophages (helping them not become nasty foam cells?) and brings it back to the liver.

Question 30

Does HDL really lower CHD risk?

Answer 30

We don’t know… People with SOME defects in HDL production (ApoA-1, LCAT) don’t have increased CHD risk. Other defects in HDL production/function (ABCA1) possibly do increase risk.