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BoD - Cardiovascular > 9Cardio > Flashcards

9Cardio Flashcards

1
Q

What are the features of Type IIb dyslipidaemias according to Frederickson’s classification?

A

Type IIb disorders have elevated levels of both LDL and VLDL, high serum cholesterol levels, high serum triglyceride levels and a high level of atherogenicity is seen. These disorders are not due to mutations in the LDL receptor.

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2
Q

What does an LDL particle contain?

A

An LDL particle contains ApoB100, cholesterol ester, unesterified cholesterol and phospholipid.

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3
Q

What types of apolipoprotein does IDL contain?

A

IDL contains ApoB100 and ApoE.

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4
Q

What types of apolipoprotein can bind to the LDL receptor?

A

ApoB100 and ApoE can both bind to the LDL receptor.

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5
Q

Which apolipoprotein has higher affinity for the LDL receptor?

A

ApoE binds with higher affinity to the LDL receptor than ApoB100 = IDL can be removed from plasma more readily than LDL

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6
Q

What is FLDB?

A

FAMILIAL LIGAND-DEFECTIVE BINDING OF APOB100 (FLDB OR FLD)

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7
Q

What are the features of FLDB?

A

Defective ApoB100 protein
Cause a genetic disorder of LDL metabolism causing hypercholesterolaemia and premature atherosclerosis due to INCREASED LDL
Phenotype is autosomal dominant and like FH in overt symptoms
Occurrence = 1/500 to 1/700 in Caucasian populations in North America and Europe. Combined heterozygosity with FH is found.
Almost all patients with FLDB are of European descent; with CGG to CAG mutation in the codon for amino acid 3500 of ApoB100
Founder effect: 6000-7000 years ago

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8
Q

Which part of the ApoB100 molecule is implicated in causing FLDB?

A

First 89% of ApoB100 wraps the LDL particle like a belt. C-terminal 11% forms a bow over the belt, bringing the C-terminal of portion of ApoB100 close to R3500
Essential interaction between Arg 3500 and Trp 4369 for normal receptor binding.
BUT these mutations are outside the LDL receptor binding site in ApoB100 (residues 3359-3369)

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9
Q

What is the model of LDL receptor binding in FLDB?

A 
Normal receptor binding in ApoB100 depends on an interaction between arginine 3500 and tryptophan 4369 (R3500-W4369)
Mutation of the arginine (FDB mutation) or the tryptophan (FDB-like mutation) disrupts receptor binding 
The R3500-W4369 interaction is essential for the correct folding of the carboxyl terminus of ApoB100 to permit normal interaction between LDL and its receptor but this interaction is not as favourable for receptor binding as removing the carboxyl tail.
LDL with ApoB97 have normal receptor binding whereas LDL with ApoB95 lack a carboxyl tail and therefore have enhanced receptor binding.
Tryptophan 4369 interacts not only with arginine 3500, but also with arginine 3480 and arginine 3531
Site B (i.e. residues 3359-3369) is the receptor-binding site.
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10
Q

What treatments are available for the treatment of FLDB?

A

Statins = to further increase removal of IDL
Fibrates = ligands activating PPARα = decrease in VLDL formation
Higher hepatic beta-oxidation causing lower VLDL synthesis = causes reduction in fatty acid synthesis and triglyceride synthesis leading to lower VLDL formation
Trials for mipomersin = antisense oligonucleotide to ApoB100 = approved for FH but causes liver damage

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11
Q

What other types of Type II hyperlipoproteinaemias are there that are caused by single gene defects (other than LDL receptor or ApoB genes)?

A

Autosomal Recessive Hypercholesterolaemia (ARH) and Autosomal Dominant Hypercholesterolaemia (ADH).

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12
Q

What are some of the features of Autosomal Recessive Hypercholesterolaemia?

A

Defective gene encodes a clathrin-coated adaptor protein = binds to LDLR
Cytoplasmic domain allows endocytosis of LDLR

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13
Q

What are some of the features of Autosomal Dominant Hypercholesterolaemia?

A

Caused by several genes
Eg. PCSK9 - pro-protein convertase subtilisin kexin type 9
Regulates LDLR function = chaperone to targeting LDLR degradation
Gain of function mutants = raised LDL-C (increased LDLR degradation)
Loss of function mutants = LDL-C down 30% (stabilising LDLR) = heart disease risk down by 90%
RECENT PHASE II CLINICAL TRIALS OF PCSK9 MAB SHOW REDUCTION OF UP TO 73% IN PLASMA LDL CHOLESTEROL LEVELS! NOW APPROVED
Only useful in hypercholesterolaemias which are not caused by a mutation in the LDL receptor

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14
Q

What is Familial Combined Hypercholesterolaemia?

A

Complex genetic disorder of LDL metabolism causing hypercholesterolaemia
Appears autosomal dominant
Elevated LDL, TG and VLDL
Premature atherosclerosis but no xanthomas
Seen from childhood but symptoms limited until 30s
FCHL estimated to be present in 1-2% of the North American population
Combined heterozygosity with FH is seen causing very severe atherosclerosis

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15
Q

What causes Familial Combined Hypercholesterolaemia and what are its diagnostic markers?

A

Primary cause unknown (LDL receptor and ApoB100 structures are normal and LDL clearance is normal)
Increased secretion rate for ApoB100 (doubling)
Higher lipidation rate and so more VLDL being produced
Microsomal Triacylglyceride Transfer Protein (MTP) thought to be more active
Catalyses the addition of TG and CE to the nascent N-terminal of ApoB
Progression of complex to the smooth ER/cis-Golgi (where bulk lipidation occurs) leading to secretion

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16
Q

What is the possible role of MTP in FCHL?

A

MTP expression stimulated by:
Dietary saturated fats
Dietary cholesterol

Results in increased VLDL secretion
Lomitapide = MTP inhibitor = approved for therapy for FH patients although does cause liver damage
FCHL treatment is same as for FLDB

17
Q

Why is FCHL so genetically complex?

A

This condition is genetically complex:
A number of associations identified with specific gene loci
May be polygenic contributions to susceptibility, variable in different families
LIPOPROTEIN LIPASE (LPL) 8p22 = convert VLDL to LDL
APO A1 CLUSTER 11q/p = includes Apo A1 (in HDL), ApoC111 (in VLDL - inhibits download by LPL) ApoAIV and ApoV
USF 1q21-23 = increase FOXA2 expression which in turn increases MTP synthesis
HNF4 = regulates MTP gene, ApoA1 and other genes in lipid and CHO metabolism (also TNF receptor)

All likely to cause and increase VLDL secretion
Links with Type II diabetes?

18
Q

What are the features of Type III Hypercholesterolaemia?

A

Raised IDL, plasma total cholesterol and triglyceride levels
Characteristic and extensive tendon xanthomas and specifically xanthomas on the palms of the hands
Premature and accelerated atherosclerosis = peripheral arteries affected as well as coronary arteries and symptoms rare until adulthood and much more prevalent in men
Presence of abnormal beta-lipoproteins, rich in cholesterol ester, known as beta-VLDL, remnants of metabolism of chylomicrons and of VLDL which are enriched in a variant, dysfunctional form of ApoE

19
Q

Which apolipoprotein is affected in type III hyperlipoproteinaemias?

A

ApoE

20
Q

How is type III hyperlipoproteinaemia inherited?

A

Autosomal dominant and recessive inheritance types found
Dominant types involve rare mutations in the receptor binding domain
Rare dominant mutations = less than 1%
Recessive types involves the common ApoE-2 isoform
Common recessive polymorphisms higher than 1%
Combined heterozygosity with FH, or with FLDB, has been found and causes very severe atherosclerosis

21
Q

What are the features of ApoE?

A

ApoE = monomeric protein of 299 residues comprising receptor binding and lipid binding domain
3 alleles are known ε2, ε3 and ε4
Population frequencies are typically (USA):
ε2 = 13%
ε3 = 76%
ε4 = 11%
These yield homozygotes with typical USA phenotype frequencies of:
Apo E2/2 = 1.3%
Apo E3/3 = 58%
Apo E4/4 = 3.0%

22
Q

What does the crystal structure of ApoE tell us about its structure?

A

Receptor binding domain in helix 4 contains solvent exposed basic amino acid residues forming a 2nm patch which binds acidic (cysteine-rich repeat) regions of LDLR and LRP (receptors necessary for lipoprotein metabolism)
ApoE-3 and -4 isoforms show very good binding for these receptors (Arg158)

23
Q

What is the difference in binding affinity between the different ApoE variants?

A

ApoE-3 and -4 isoforms show very good binding for these receptors (Arg158)
ApoE-3 (IDL) binds 25x tighter to LDLR than LDL
ApoE-2 (IDL) binds with equal affinity to LDLR as LDL

24
Q

What is the importance of the amino acid 158 in salt bridge formation of ApoE?

A

It is important that amino acid 158 is capable of forming a salt bridge with Asp154. If it does not, Asp154 will form a salt bridge with Arg150. This is what happens in the E2 form of ApoE and accounts for its lower binding affinity. In the E3 form, on the other hand, Arg158 forma a salt bridge with Asp154; this prevents it from forming a salt bridge with Arg150 and thus stops it from interfering with the LDL-receptor binding domain.

25
Q

Which variant of ApoE do Type III Hyperlipoproteinaemia patients typically have? What else contributes to their increased risk of developing atherosclerosis?

A

Most Type III patients are homozygous for ApoE-2 isoform (apoE2/E2)
Detectable “β-VLDL” but not pathological levels
But only 1-5% apoE2/2 are Type III
OTHER FACTORS ARE NEEDED (genetic and environmental) that exacerbate the hyperlipoproteinaemia
Homozygosity for ApoE2 is a necessary, but not sufficient to cause Type III hyperlipoproteinaemia

26
Q

What are some of the rare mutations which can occur in ApoE?

A

Rare mutations exist for basic residues - R136S, R142C, R145C and L146Q/E - all disrupt receptor binding and cause dominant Type III phenotype
Expression of mutant ApoE with defective binding to receptors is an absolute requirement for expression of Type III disease

27
Q

How is ApoE connected to the metabolism of chylomicron remnants in the liver?

A

Chylomicron remnants are internalised into the liver via ApoE. They may enter the liver either via LDL receptors or via the LRP/HSPG pathway.

28
Q

How do Heparan Sulphate Proteoglycans play a role in the metabolism of chylomicron remnants in the liver?

A

HSPG are abundant in the space of Disse and on the surface of hepatocytes
ApoE and HL, secreted by the hepatocytes, appear to bind to the HSPG and be available to enrich lipoproteins
The HSPG/ApoE appear to fulfill a critical role in the sequestration or capture of the remnants

29
Q

What are the three major pathways for internalisation of chylomicron remnants?

A

Three major pathways for internalisation are illustrated:
Direct uptake by LDL receptor
HSPG-LRP pathway = a) remnants transferred to LRP for uptake b) HSPG-LRP complex internalised
HSPG alone mediating direct uptake

30
Q

How is chylomicron remnant metabolsim affected in ApoE2/E2 or ApoE mutants?

A

ApoE2/E2 or ApoE mutants have reduced uptake of chylomicron remnants via LDLR or HSPG-LRP pathway.

31
Q

What is the interplay between IDL and ApoE metabolism in the liver?

A

IDL and ApoE can COMPETE for binding to liver LDLR.
ApoE2/E2 or ApoE mutants have reduced uptake of chylomicron remnants via LDLR or HSPG-LRP pathway.
Any conditions depressing LDLR activity will amplify increases in IDL and LDL in ApoE2/E2 homozygotes:
Fat rich diet, obesity and diabetes
Low levels of oestrogen, age and hypothyroidism
ALL these factors reduce the expression of LDLR
ApoB100-mediated clearance via LDLR becomes more important in the ApoE2/E2 homozygotes.

32
Q

Why are effects so severe if heterozygote with FH or FDB?

A

If LDL receptor is also affected clearance of lipoproteins will be minimal. If ApoB100 is affected it will be very difficult for anything to bind to the LDLR (if ApoE is also affected).

33
Q

What is the treatment for Type III Hypercholesterolaemias?

A

Treatment:
Statins = to further increase removal of IDL
Usually combined with fibrates = to decrease synthesis of VLDL
Diet to reduce chylomicron formation

34
Q

What is a summary of Type III Hypercholesterolaemias?

A

Elevated cholesterol and triglycerides
Homozygosity for ApoE2 is a necessity but by itself is not enough to cause Type III hyperlipoproteinaemia (recessive inheritance)
Rare mutations of ApoE cause Type II Hyperlipoproteinaemias (dominant inheritance)
Reduced uptake of chylomicron remnants and IDL
Increase in plasma triglycerides and cholesterol (IDL)
Leads to atherosclerosis

BoD - Cardiovascular (4 decks)

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