Cholesterol and Lipoprotein Metabolism Flashcards
Which particle(s) contains ApoB-48?
Only chylomicrons. (and chylomicron remnants)
Which particle(s) contains ApoB-100?
VLDL, IDL, and LDL
Which particle(s) contains ApoE?
VLDL and HDL (and chylomicron remnants)
Which particle(s) contains ApoC-II?
Chylomicrons and VLDL
What makes the absorption of fats in chylomicrons via lymphatics special compared to the absorption of other nutrients?
These lymphatics bypass the liver, and fat can go straight to adipose for storage.
When a chylomicron transitions to a chylomicron remnant, what lipoprotein(s) does it lose/gain?
It loses ApoC-II and picks up ApoE.
How is are chylomicron remnants taken up by the liver?
The LDL receptor (LDLR) in hepatocytes binds ApoE on chylomicron remnants.
What form of ApoB does this liver make? (and thus, what’s on all the transport particles made by the liver?)
ApoB-100
What does LDLR recognize to take up particles?
ApoB-100 and ApoE
7 non-genetic (“secondary”) causes of hyperlipoproteinemia?
not a list to memorize, but it shouldn’t surprise you
Diet Alcohol (-> high TGs) Insulin resistance / T2DM Hypothyroidism Nephrotic syndrome Chronic renal failure Meds (lots of them)
What’s the mechanism for insulin resistance / T2DM leading to hyperlipoproteinemia?
Because glucose can’t be used, free fatty acids (FFAs) are liberated.
Increased FFA flux to liver leads to increased VLDL production.
Which mutations cause Familial Chylomicronemia Syndromes? How? What “Frederickson/Levy” type are these?
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.
What skin lesion is associated with Familial Chylomicronemia Syndromes (esp. LPL deficiency)? When will they erupt?
Eruptive xanthomas are associated with lipoprotein lipase deficiency. Eruptions tend to occur after high TG intake.
What’s the major clinical issue associated with chylomicrons being too high?
Pancreatitis.
What’s the genetic mutation in Familial dysbetalipoproteinemia? (it’s a poor name)
What “type” is this?
ApoE - such that it can’t bind LDLR.
This is Type III.
What two processes is ApoE very important in? What do patients with ApoE mutations thus have in their blood?
Chylomicron remnant clearance.
IDL uptake into liver.
Pts without functional ApoE have high levels of “remnants” i.e. chylomicron remnants, and LDL.
What skin lesions are associated with ApoE defects / aka dysbetalipoproteinemia / aka Type III hyperlipoproteinemia?
Tuberous xanthomas.
Palmar xanthomas.
What clinical problem is associated with ApoE defects?
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)
What’s defective in Familial hypercholesteremia (FH)?
What “type” of hyperlipoproteinemia is this?
LDLR defect (heterozygous is bad, homozygous is worse). This is Type IIa hyperlipoproteinemia.
Which xanthomas are most specifically associated with FH?
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.)
When do you see cutaneous xanthomas?
homozygous FH
What do ApoB-100 mutations act just like? Why?
ApoB-100 is the ligand on LDL for LDLR.
Thus, ApoB-100 mutations “phenocopy” FH.
What is mutated in autosomal dominant hypercholesterolemia 3 (ADH3)? What hyperlipoproteinemia type is this?
Pcsk9, with a gain of function mutation.
This is also type IIa hyperlipoproteinemia.
What effect does a gain of function mutation in Pcsk9 have? Why is this effect dominant?
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.
What causes familial hypertriglyceridemia? Which hyperlipoproteinemia type is this?
Defects in processing VLDL (removing TGs from the particles.)
This is type IV or V, where V is more severe.
But wait. Doesn’t a defect in removing TGs from particles also cause familial hyperchylomicronemia?
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.)
What is elevated in Familial combined hyperlipidemia? What hyperlipoproteinemia type is this?
VLDL production is increased, but this also leads to elevations in LDL. This is Type IIb.
(the etiology is unknown)
What’s the deal with lipoprotein(a) “little a”?
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…
Why has HDL long been though to be protective against atherosclerotic disease?
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.
Does HDL really lower CHD risk?
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.
