T15 - Disorders of Cholesterol Metabolism Flashcards
Describe the effects of LDL and atherosclerosis on coronary arteries. (9)
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
What is angina?
pain that results from occlusion of coronary artery by atherosclerotic lesions
Atherosclerosis leads to scarring on the arterial wall. What happens if the fibrous scab covering the scar ruptures? (2)
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
The risk of myocardial infarction has what relationship to plasma LDL-C levels?
risk of heart attack is linearly related to plasma LDL-C levels
How does hepatic lipase remodel VLDLrs/IDLs?
gets rid of remaining TGs + some phospholipids and cholesterols on surface, producing LDL, which is mostly cholesterol esters + ApoB-100
What is the fate of the cholesterol esters that are endocytosed into cells as part of LDL?
cholesterol esters de-esterified by acid lipase and free cholesterol is delivered to ER for steroid/membrane/bile acid synthesis
What must happen to free cholesterol that enters the cell destined for storage in a lipid droplet?
must be esterified by ACAT, an enzyme located in the ER
What protein regulates cholesterol in cells? Explain its mechanism.
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
What is the genetic basis of familial hypercholesterolemia?
mutation in LDLR
Describe the difference between heterozygous and homozygous familial hypercholesterolemia.
[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]
How do LDLR mutations affect the rate of LDL production?
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
Why do LDLR mutations result in higher plasma LDL levels?
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
What is the frequency of familial hypercholesterolemia heterozygotes?
1 in 250
What fraction of familial hypercholesterolemia LDLR mutations impair and completely inactivate LDLR?
30% completely inactivate
70% impair
Describe the effects of familial hypercholesterolemia on TG levels in FH heterozygotes.
No effect, TG levels are normal because LDLs don’t really have TG to begin with
What are the four primary clinical presentations of familial hypercholesterolemia heterozygotes?
arcus cornea
xanthelasma
tendon xanthomas
coronary atherosclerosis
Describe arcus cornea as a clinical presentation of familial hypercholesterolemia heterozygotes.
cholesterol accumulates in cornea
suggestive of, but not diagnostic of, familial hypercholesterolemia
Describe xanthelasma as a clinical presentation of familial hypercholesterolemia.
cholesterol accumulation under eyes
suggestive of, but not diagnostic of, familial hypercholesterolemia
also seen in type III hyperlipoproteinemia
Describe tendon xanthomas as a clinical presentation of familial hypercholesterolemia.
enlargement of tendons of ankle/hands/elbow
cholesterol accumulates in macrophages, producing foam cells
When do familial hypercholesterolemia patients start having heart attacks as a result of coronary atherosclerosis?
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
What are the three primary clinical presentations of homozygous familial hypercholesterolemia?
planar xanthomas
xanthomas in webs between fingers (diagnostic of FH)
heart attacks as young as 18 months of age
Describe planar xanthomas as a clinical presentation of homozygous familial hypercholesterolemia.
yellow, nonvisible cutaneous xanthomas behind heel, on buttocks, elbow etc.
increased endothelial damage
macrophage activity → foam cells
How are familial hypercholesterolemia homozygotes diagnosed? (2)
(1) lipid profile and inheritance pattern in family
(2) exon sequencing of genome
How do statins treat familial hypercholesterolemia heterozygotes?
inhibit cholesterol synthesis by blocking HMG-CoA reductase → activate SREPB-2 → increased expression of LDLR
How does ezetimibe treat familial hypercholesterolemia heterozygotes?
blocks cholesterol absorbed in enterocytes → overall, reduces dietary cholesterol delivered to liver → increase in SREBP-2 → increase in LDLR expression
How do bile acid resins treat familial hypercholesterolemia heterozygotes?
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
Why are bile acid resins often given in combination with statins?
though bile acid resins increase LDLR expression, they also increase cholesterol expression, so statins help reduce the latter
What are the three major treatment options for familial hypercholesterolemia heterozygotes?
statins
ezetimibe
bile acid resins
What are the two primary treatment options for familial hypercholesterolemia homozygotes?
liver transplant (but risky because of patient rejection)
LDL apheresis (like dialysis, using anti-ApoB antibodies to clear blood of LDL)
Mutations in the ligand binding domain of ApoB-100 lead to
inability of LDL to bind to LDLR, causing dominantly-inherited hypercholesterolemia
What is PCSK9?
protein synthesized by hepatocytes and secreted into blood
What is the function of PCSK9?
circulates in blood and binds to LDLR on surface of hepatocytes
Describe what happens when PCSK9 binds to LDLR.
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
What are three genetic defects that lead to hypocholesterolemia?
abetalipoproteinemia
hypobetalipoproteinemia
PCKS9 inactivating mutation
Abetalipoproteinemia is what kind of disorder?
rare autosomal recessive
What causes abetalipoproteinemia?
mutations that inactivate MTTP (which transfers TG to ApoB-48 in nascent CMs or transfers TG to ApoB-100 in nascent VLDLs)
What is the result of abetalipoproteinemia? (3)
can’t synthesize VLDL or CM without MTTP
dietary TG can’t be absorbed, including fat-soluble vitamins
fatty liver
Hypobetalipoproteinemia is what kind of disorder?
autosomal dominant disorder
What causes hypobetalipoproteinemia?
caused by mutations that interfere w/ production of ApoB (therefore affects VLDL, CM, IDL, and LDL production)
Differentiate between hypobetalipoproteinemia heterozygotes and homozgyotes.
heterozygotes: >50% reduction in [LDL-C]
homozgyotes: same clinical presentation as abetalipoproteinemia
Why does an inactivating mutation of PCSK9 result in hypocholesterolemia?
inactivated PCSK9 means that LDLR receptors are getting recycled more than usual, meaning more uptake of cholesterol, meaning less cholesterol in plasma
Why does CETP deficiency lead to higher plasma cholesterol?
CETP is supposed to exchange CEs from HDL with TGs from VLDL/IDL, so if CETP is blocked, then CEs in HDL accumulate
What is the relationship between HDL and CAD? (4)
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]
What is the significance of extrapolating this curve to the x-intercept?
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
(T/F) If LDLRs are completely inactivated, LDL-C will remain stuck in the circulation forever.
False. There are nonspecific pathways that can uptake LDL-C if LDLRs don’t work — it will just take a lot longer.
Broadly speaking, which portion of the human LDL receptor is responsible for endocytosis?
the C-terminus side in the cytoplasm
What are the 5 types of LDLR mutations?
mutations in:
synthesis
transport
binding
clustering
recycling
What is the most common clinical finding used to definitively diagnose familial hypercholesterolemia?
tendon xanthomas
