Lipoproteins and Hyperlipoproteinemias Flashcards
What is the function of LCAT? What is needed to active it?
LCAT = Lecithin cholesterol acyltransferase
Esterifies plasma cholesterol released from tissues so they can be uptaken by HDL (they will be hydrophobic enough)
Needs Lipoprotein A-1 to activate it.
A1 = Activates
Apo-AI is considered the principle protein in HDl
On what particles does ApoE exist and what is its function?
“E”verything “E”xcept LDL
- > LDL doesn’t have one because liver has LDL scavenger receptor
- > ApoE is used to pick up remnants of other lipoproteins
What is the primary apolipoprotein on chylomicrons and its function?
Apo B-48 -> mediates its secretion into lymphatics
Found only in chylomicron + chylomicron remnants
What is the function of Apolipoprotein C-II and what particles is it present on?
VLDL, HDL, Chylomicrons -> “C”ofactor for “C”leavage -> required for activity of vascular endothelial lipoprotein lipase (LPL) to free fatty acids from VLDL / chylomicrons for tissue uptake
What is the function of B100?
Packaged with VLDL by liver, it will also be present in IDL and LDL.
Function: Binds the LDL receptor on liver (since no Apo-E is present). Receptor is the apo B/E receptor
What type of LDL particle has unknown physiologic function but has been demonstrated to be an independent risk factor for atherosclerosis / CAD?
Lipoprotein (a) [Lp(a)]
List the lipoprotein particles from most to least triglycerides. Which one has the most cholesterol and which apoprotein does it express?
Chylomicrons > VLDL > IDL > LDL > HDL
LDL has the most cholesterol - expresses only Apo B100
Note: HDL is higher density because it expresses many more apoproteins than LDL
What is the function of hepatic triglyceride lipase?
Degrades the remaining triglycerides in chylomicrons -> chlyomicron remnants, as well as IDL -> LDL
What is the function of CETP? Why might blockage be useful?
Cholesterol Ester Transfer Protein - Functions to transfer cholesterol esters from HDL to VLDL / IDL / chylomicron remnants
-> blockage could ultimately stop the formation of LDL particles, which get concentrated with cholesterol from HDL transfer via CETP
What is the underlying defect in familial hypercholesterolemia (most commonly)? What is the inheritance pattern?
Mutation in LDL receptor which results in receptor deficiency or dysfunction -> elevations in plasma LDL and total cholesterol
Inheritance pattern is autosomal dominant, with homozygous disease being much worse than heterozygous. Heterozygotes are common (1/500)
What are the clinical features of heterozygotes FH (Type II dyslipidemia)?
Premature heart disease / accelerated atherosclerosis
Physical signs:
1. Xanthelasmas - cholesterol depositions around the eyes
2. Tendonous xanthomas - extensor tendons of the hands, Achilles tendon
3. Premature corneal arcus
What are the clinical features of homozygous FH?
Same features as heterozygous form (xanthelasmas, xanthomas, arcus corneae) +
- Early life CHD + hypercholesterolemia (cholesterol 700+)
- Early MI’s
- Plantar xanthomas! unique for homozyogous -> knees, elbows, areas of skin trauma
What is the function of PCSK9?
PCSK9 maintains association of LDLR with LDL when the LDL goes to be degraded by lysosome -> LDLR gets degraded too.
Blockers of this protein are Evolocumab and Alirocumab
What is familial combined hyperlipidemia?
An autosomal dominant inheritance of moderate elevations of triglycerides and total cholesterol
-> unknown genetic cause, but is demonstrable clinically
What are the clinical features of familial combined hyperlipidemia?
Premature CHD w/ family history of premature CHD
Xanthomas and xanthelasmas will be ABSENT
-> associated with obesity, glucose intolerance, diabetes
What is Type III hyperlipoproteinemia and what is the inheritance pattern? Mechanism?
Dysbetalipoproteinemia - rare autosomal recessive condition of ApoE defect
- > Chylomicrons, VLDL, and IDL do not properly bind the LDL receptor (Apo B/E receptor)
- > Increased blood levels of these remnants increases triglycerides and total cholesterol
REMEMBER it’s dysBETAlipoproteinemia because lipids of the B-48 and B-100 lineages are abnormal (defective ApoE). LDL is okay because there is no ApoE, and where does HDL even come from lol.
What is the pathognomonic feature of dysbetalipoproteinemia?
Palmar xanthomas
-> think of xanthomas which make an E shape on the creases of the palms
ApoE = 3 (looks like roman numeral 3), and E on the palms
What other problems will dysbetalipoproteinemia have other than palmar xanthomas?
Premature atherosclerosis (greatly increased cholesterol) and tuberous xanthomas (large bullous vesicles on elbows due to increased triglycerides)
What is Type I dyslipidemia also called and what are the two causes? Inheritance pattern?
Hyperchylomicronemia - autosomal recessive
Increased chylomicrons, and triglyceride levels due to either:
1. Lipoprotein lipase deficiency
or
2. Apolipoprotein C-II deficiency (co-factor for LPL)
What are the clinical findings of hyperchylomicronemia? Is there an increased risk of atherosclerosis?
- Pancreatitis -> due to high triglycerides
- Hepatosplenomegaly
- Eruptive xanthomas - papules on buttocks and back due to triglyceride accumulates
- Lipemia retinalis - capillaries in back of eye look white
Is there increased risk of atherosclerosis in hyperchylomicronemia? What can be seen in the supernatant of the blood?
The supernatant is creamy due to increased triglycerides
Atherosclerosis risk is NOT increased
What is Type IV dyslipidemia called and what causes it? Inheritance pattern?
Hypertriglyceridemia -> autosomal DOMINANT due to overproduction of VLDL
What will be seen clinically in hypertriglyceridemia?
High TGs with risk of pancreatitis if TGs > 1000 mg/dL
Eruptive xanthomas -> similar reasoning as hyperchylomicronemia
What is secondary lipoproteinemia and how can diabetes cause it?
Lipoproteinemia due to a secondary underlying disorder
Uncontrolled DM: insulin deficiency will decrease LPL activity and thus decreases VLDL clearance. Peripheral lipolysis also increases LDL synthesis.
How does hypothyroidism caause secondary lipoproteinemia? Why is this clinically relevant?
- Low BMR slows LPL activity
- LDL levels increased due to lack of T4 stimulation of SREBP2
Relevant because hyperlipidemia repsonds very well to T4 replacement therapy -> should be screening for hypothyroidism especially in young females with dyslipidemia
How do estrogen and alcohol affect lipoproteins?
Estrogen -> Decrease LDL and Increase HDL, but somehow increase CV risk
Alcohol -> increases fatty (TG synthesis) in excess -> increases VLDL. In moderation, may increase HDL.
How does nephrotic syndrome affect lipids?
Increased VLDL and LDL via liver hypersecretion due to proteinuria
What drugs cause secondary lipoproteinemias?
- Protease inhibitors - i.e. ritonavir
- Glucocorticoids -> destroy LPL function and LDL clearance
- Androgens -> decrease HDL and increase LDL
- Thiazides -> hypertriglyceridemia
- Beta blockers -> increased LDL + TGs, decreased HDL. Beta with selective B1 blockers.
What is the recommendation for hyperlipidemia screening?
Complete fasting lipid profile in ll adults over age 20, repeated every 5 years.
Start earlier if family history of dyslipidemia / CHD.
