Lipoproteins and Hyperlipoproteinemias

Question 1

What is the function of LCAT? What is needed to active it?

Answer 1

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

Question 2

On what particles does ApoE exist and what is its function?

Answer 2

“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

Question 3

What is the primary apolipoprotein on chylomicrons and its function?

Answer 3

Apo B-48 -> mediates its secretion into lymphatics

Found only in chylomicron + chylomicron remnants

Question 4

What is the function of Apolipoprotein C-II and what particles is it present on?

Answer 4

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

Question 5

What is the function of B100?

Answer 5

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

Question 6

What type of LDL particle has unknown physiologic function but has been demonstrated to be an independent risk factor for atherosclerosis / CAD?

Answer 6

Lipoprotein (a) [Lp(a)]

Question 7

List the lipoprotein particles from most to least triglycerides. Which one has the most cholesterol and which apoprotein does it express?

Answer 7

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

Question 8

What is the function of hepatic triglyceride lipase?

Answer 8

Degrades the remaining triglycerides in chylomicrons -> chlyomicron remnants, as well as IDL -> LDL

Question 9

What is the function of CETP? Why might blockage be useful?

Answer 9

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

Question 10

What is the underlying defect in familial hypercholesterolemia (most commonly)? What is the inheritance pattern?

Answer 10

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)

Question 11

What are the clinical features of heterozygotes FH (Type II dyslipidemia)?

Answer 11

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

Question 12

What are the clinical features of homozygous FH?

Answer 12

Same features as heterozygous form (xanthelasmas, xanthomas, arcus corneae) +

1. Early life CHD + hypercholesterolemia (cholesterol 700+)
2. Early MI’s
3. Plantar xanthomas! unique for homozyogous -> knees, elbows, areas of skin trauma

Question 13

What is the function of PCSK9?

Answer 13

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

Question 14

What is familial combined hyperlipidemia?

Answer 14

An autosomal dominant inheritance of moderate elevations of triglycerides and total cholesterol
-> unknown genetic cause, but is demonstrable clinically

Question 15

What are the clinical features of familial combined hyperlipidemia?

Answer 15

Premature CHD w/ family history of premature CHD

Xanthomas and xanthelasmas will be ABSENT

-> associated with obesity, glucose intolerance, diabetes

Question 16

What is Type III hyperlipoproteinemia and what is the inheritance pattern? Mechanism?

Answer 16

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.

Question 17

What is the pathognomonic feature of dysbetalipoproteinemia?

Answer 17

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

Question 18

What other problems will dysbetalipoproteinemia have other than palmar xanthomas?

Answer 18

Premature atherosclerosis (greatly increased cholesterol) and tuberous xanthomas (large bullous vesicles on elbows due to increased triglycerides)

Question 19

What is Type I dyslipidemia also called and what are the two causes? Inheritance pattern?

Answer 19

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)

Question 20

What are the clinical findings of hyperchylomicronemia? Is there an increased risk of atherosclerosis?

Answer 20

1. Pancreatitis -> due to high triglycerides
2. Hepatosplenomegaly
3. Eruptive xanthomas - papules on buttocks and back due to triglyceride accumulates
4. Lipemia retinalis - capillaries in back of eye look white

Question 21

Is there increased risk of atherosclerosis in hyperchylomicronemia? What can be seen in the supernatant of the blood?

Answer 21

The supernatant is creamy due to increased triglycerides

Atherosclerosis risk is NOT increased

Question 22

What is Type IV dyslipidemia called and what causes it? Inheritance pattern?

Answer 22

Hypertriglyceridemia -> autosomal DOMINANT due to overproduction of VLDL

Question 23

What will be seen clinically in hypertriglyceridemia?

Answer 23

High TGs with risk of pancreatitis if TGs > 1000 mg/dL

Eruptive xanthomas -> similar reasoning as hyperchylomicronemia

Question 24

What is secondary lipoproteinemia and how can diabetes cause it?

Answer 24

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.

Question 25

How does hypothyroidism caause secondary lipoproteinemia? Why is this clinically relevant?

Answer 25

1. Low BMR slows LPL activity
2. 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

Question 26

How do estrogen and alcohol affect lipoproteins?

Answer 26

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.

Question 27

How does nephrotic syndrome affect lipids?

Answer 27

Increased VLDL and LDL via liver hypersecretion due to proteinuria

Question 28

What drugs cause secondary lipoproteinemias?

Answer 28

1. Protease inhibitors - i.e. ritonavir
2. Glucocorticoids -> destroy LPL function and LDL clearance
3. Androgens -> decrease HDL and increase LDL
4. Thiazides -> hypertriglyceridemia
5. Beta blockers -> increased LDL + TGs, decreased HDL. Beta with selective B1 blockers.

Question 29

What is the recommendation for hyperlipidemia screening?

Answer 29

Complete fasting lipid profile in ll adults over age 20, repeated every 5 years.

Start earlier if family history of dyslipidemia / CHD.