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Tissues > T15 - Disorders of Cholesterol Metabolism > Flashcards

T15 - Disorders of Cholesterol Metabolism Flashcards

1
Q

Describe the effects of LDL and atherosclerosis on coronary arteries. (9)

A

LDL/VLDL/CMrs diffuse from blood into subendothelial tissue → circulating monocytes follow into the arterial wall → monocytes become retained and are now macrophages that consume lipoproteins → chronic, low grade inflammation → formation of foam cells (macrophages filled with lipids) → cell death → cholesterol crystals released into tissue → fatty streaks on endothelial lining → scarring and blood flow occlusion

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2
Q

What is angina?

A

pain that results from occlusion of coronary artery by atherosclerotic lesions

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3
Q

Atherosclerosis leads to scarring on the arterial wall. What happens if the fibrous scab covering the scar ruptures? (2)

A

lipid in lesion/plaque will now interact with blood and form a clot that occludes the artery, leading to myocardial infarction → heart attack

if this happens to one of the cerebral arteries → cerebral infarction → stroke

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4
Q

The risk of myocardial infarction has what relationship to plasma LDL-C levels?

A

risk of heart attack is linearly related to plasma LDL-C levels

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5
Q

How does hepatic lipase remodel VLDLrs/IDLs?

A

gets rid of remaining TGs + some phospholipids and cholesterols on surface, producing LDL, which is mostly cholesterol esters + ApoB-100

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6
Q

What is the fate of the cholesterol esters that are endocytosed into cells as part of LDL?

A

cholesterol esters de-esterified by acid lipase and free cholesterol is delivered to ER for steroid/membrane/bile acid synthesis

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7
Q

What must happen to free cholesterol that enters the cell destined for storage in a lipid droplet?

A

must be esterified by ACAT, an enzyme located in the ER

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8
Q

What protein regulates cholesterol in cells? Explain its mechanism.

A

SREBP-2 is a transcription factor that is inhibited by cholesterol in the cell

SREBP-2 regulates expression of genes involved in cholesterol synthesis (i.e. enzyme HMG CoA reductase) + expression of LDLRs

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9
Q

What is the genetic basis of familial hypercholesterolemia?

A

mutation in LDLR

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10
Q

Describe the difference between heterozygous and homozygous familial hypercholesterolemia.

A

[heterozygous] one mutated allele means 50% of normal # of LDLR present on cell surface, and therefore 2x higher plasma [LDL-C]

[homozygous] both mutated alleles mean basically no functional LDLRs, and therfore 6-10x higher plasma [LDL-C]

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11
Q

How do LDLR mutations affect the rate of LDL production?

A

mutation in LDLR results in increase of rate of LDL production because a higher fraction of IDL is being converted to LDL via HL rather than hepatic LDLR clearance

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12
Q

Why do LDLR mutations result in higher plasma LDL levels?

A

twofold:

(1) increased rate of production because more IDL is being converted to LDL via HL instead of hepatic clearance
(2) decrease in rate of LDL clearance because of nonfunctional LDLR

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13
Q

What is the frequency of familial hypercholesterolemia heterozygotes?

A

1 in 250

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14
Q

What fraction of familial hypercholesterolemia LDLR mutations impair and completely inactivate LDLR?

A

30% completely inactivate

70% impair

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15
Q

Describe the effects of familial hypercholesterolemia on TG levels in FH heterozygotes.

A

No effect, TG levels are normal because LDLs don’t really have TG to begin with

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16
Q

What are the four primary clinical presentations of familial hypercholesterolemia heterozygotes?

A

arcus cornea

xanthelasma

tendon xanthomas

coronary atherosclerosis

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17
Q

Describe arcus cornea as a clinical presentation of familial hypercholesterolemia heterozygotes.

A

cholesterol accumulates in cornea

suggestive of, but not diagnostic of, familial hypercholesterolemia

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18
Q

Describe xanthelasma as a clinical presentation of familial hypercholesterolemia.

A

cholesterol accumulation under eyes

suggestive of, but not diagnostic of, familial hypercholesterolemia

also seen in type III hyperlipoproteinemia

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19
Q

Describe tendon xanthomas as a clinical presentation of familial hypercholesterolemia.

A

enlargement of tendons of ankle/hands/elbow

cholesterol accumulates in macrophages, producing foam cells

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20
Q

When do familial hypercholesterolemia patients start having heart attacks as a result of coronary atherosclerosis?

A

men start having heart attacks in their 30s (~15 years before women do)

50% of untreated familial hypercholesterolemia heterozygous men have heart attacks before age 60

21
Q

What are the three primary clinical presentations of homozygous familial hypercholesterolemia?

A

planar xanthomas

xanthomas in webs between fingers (diagnostic of FH)

heart attacks as young as 18 months of age

22
Q

Describe planar xanthomas as a clinical presentation of homozygous familial hypercholesterolemia.

A

yellow, nonvisible cutaneous xanthomas behind heel, on buttocks, elbow etc.

increased endothelial damage

macrophage activity → foam cells

23
Q

How are familial hypercholesterolemia homozygotes diagnosed? (2)

A

(1) lipid profile and inheritance pattern in family
(2) exon sequencing of genome

24
Q

How do statins treat familial hypercholesterolemia heterozygotes?

A

inhibit cholesterol synthesis by blocking HMG-CoA reductase → activate SREPB-2 → increased expression of LDLR

25
Q

How does ezetimibe treat familial hypercholesterolemia heterozygotes?

A

blocks cholesterol absorbed in enterocytes → overall, reduces dietary cholesterol delivered to liver → increase in SREBP-2 → increase in LDLR expression

26
Q

How do bile acid resins treat familial hypercholesterolemia heterozygotes?

A

resins bind to bile acids in gut lumen such that bile acids are excreted rather than reclaimed in gut → liver upgregulates LDLR to obtain more cholesterol for bile acid synthesis

27
Q

Why are bile acid resins often given in combination with statins?

A

though bile acid resins increase LDLR expression, they also increase cholesterol expression, so statins help reduce the latter

28
Q

What are the three major treatment options for familial hypercholesterolemia heterozygotes?

A

statins

ezetimibe

bile acid resins

29
Q

What are the two primary treatment options for familial hypercholesterolemia homozygotes?

A

liver transplant (but risky because of patient rejection)

LDL apheresis (like dialysis, using anti-ApoB antibodies to clear blood of LDL)

30
Q

Mutations in the ligand binding domain of ApoB-100 lead to

A

inability of LDL to bind to LDLR, causing dominantly-inherited hypercholesterolemia

31
Q

What is PCSK9?

A

protein synthesized by hepatocytes and secreted into blood

32
Q

What is the function of PCSK9?

A

circulates in blood and binds to LDLR on surface of hepatocytes

33
Q

Describe what happens when PCSK9 binds to LDLR.

A

LDLR-PCSK9 complex gets endocytosed

however, as a result of binding to PCSK9, LDLR gets degraded rather than recycled to cell surface

leads to hypercholesterolemia

34
Q

What are three genetic defects that lead to hypocholesterolemia?

A

abetalipoproteinemia

hypobetalipoproteinemia

PCKS9 inactivating mutation

35
Q

Abetalipoproteinemia is what kind of disorder?

A

rare autosomal recessive

36
Q

What causes abetalipoproteinemia?

A

mutations that inactivate MTTP (which transfers TG to ApoB-48 in nascent CMs or transfers TG to ApoB-100 in nascent VLDLs)

37
Q

What is the result of abetalipoproteinemia? (3)

A

can’t synthesize VLDL or CM without MTTP

dietary TG can’t be absorbed, including fat-soluble vitamins

fatty liver

38
Q

Hypobetalipoproteinemia is what kind of disorder?

A

autosomal dominant disorder

39
Q

What causes hypobetalipoproteinemia?

A

caused by mutations that interfere w/ production of ApoB (therefore affects VLDL, CM, IDL, and LDL production)

40
Q

Differentiate between hypobetalipoproteinemia heterozygotes and homozgyotes.

A

heterozygotes: >50% reduction in [LDL-C]
homozgyotes: same clinical presentation as abetalipoproteinemia

41
Q

Why does an inactivating mutation of PCSK9 result in hypocholesterolemia?

A

inactivated PCSK9 means that LDLR receptors are getting recycled more than usual, meaning more uptake of cholesterol, meaning less cholesterol in plasma

42
Q

Why does CETP deficiency lead to higher plasma cholesterol?

A

CETP is supposed to exchange CEs from HDL with TGs from VLDL/IDL, so if CETP is blocked, then CEs in HDL accumulate

43
Q

What is the relationship between HDL and CAD? (4)

A

generally, lower HDL leads to CAD*,**

*however, it has not been shown that the reverse is true (i.e. higher HDL does not necessarily reduce CAD)

**however, genetic mutations (LCAT or ApoAI mutations) that lead to lower HDL do not necessarily induce CAD

[unlike LDL-C, in which all disorders that increase LDL-C lead to increase in CAD]

44
Q

What is the significance of extrapolating this curve to the x-intercept?

A

estimate x-intercept as 60 mg/dL

theoretically, it would mean that a patient with 60 mg/dL plasma [LDL-C] would be immune from CHD

45
Q

(T/F) If LDLRs are completely inactivated, LDL-C will remain stuck in the circulation forever.

A

False. There are nonspecific pathways that can uptake LDL-C if LDLRs don’t work — it will just take a lot longer.

46
Q

Broadly speaking, which portion of the human LDL receptor is responsible for endocytosis?

A

the C-terminus side in the cytoplasm

47
Q

What are the 5 types of LDLR mutations?

A

mutations in:

synthesis

transport

binding

clustering

recycling

48
Q

What is the most common clinical finding used to definitively diagnose familial hypercholesterolemia?

A

tendon xanthomas

Tissues (23 decks)

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