Familial Hypercholesterolemia & CHD Flashcards
What is CHD?
Underling cause is atherosclerosis of coronary arteries
10% of deaths in UK (2024)
Lipoprotein Structure
- Have surface monolayer of phospholipid, nonesterified cholesterol and protein
- Have core of cholesteryl ester and triglyceride and some non esterified cholestrol
Main type of lipoproteins
- Chylomicrons
- Very low density lipoproteins (VLDL)
- Low density lipoproteins (LDL)
- High density lipoproteins (HDL)
LDL
- 25nm in diameter
- 75% lipid , 25% protein
LDL Receptor Pathway
LDL taken up by receptors by receptor mediated endocytosis
LDL receptor binds to apolipoprotein B-100 on LDL particles
Acidity
LDL dissociates from receptor at acidic pH
- Closed conformation, less freedom of movement
LDL Receptor Cycles
~ 20 min for 1 complete cycle
~ around 100 cycles completed in lifetime
Regulation of LDL receptor
LDL receptor gene
- short arm of chromosome 19
- 18 exons, 17 introns
-45 kb
Exons
Exon 1: Codes for 21 AA
Exon 2-6: Codes for ligand-binding domain
Exon 7-14: Codes for domain homologous to EGF precursor required for dissociation at acidic pH
Exon 15: Codes for domain with o-linked oligosaccharides attached
Exon 16 and part 17: Codes for membrane spanning domain
Remainer of 18 and part 19: Cytosolic domain
Remainded - untranslated
Familial Hypercholesterolemia
- Most common monogenic genetic disease, almost always autosomal dominant genetic disease
- 50% risk of CHD at 50 years (men)
- 30% risk at 60 years (women)
LDL Receptor Mutatations
- 90% of cases are due to LDL receptor mutations
- 1800 different mutations discovered
- 65% point mutations
- 24% are small DNA rearrangements
- 11% are major structural rearrangements (deletions or insertions)
Class 1
Synthesis, little to no LDL rec protein produced, mutation in promoter, some produce low conc of normal or truncated mRNA, ~15% of mutations
Class 2
Defective transfer from ER to golgi complex, mutation in lig-binding domain or EFG precursor hom domain, ~ 50% of mutations.
Class 3
Defective binding of LDL, ~25% of mutations
Class 4
Rare, mutations in cytoplasmic domain, LDL receptors distributed diffusely on cell surface, do not cluster in coated pits
Class 5
Recycling defective mutations
Animal Models
WHHL Rabbit:
- Class 2 mutation, severe atherosclerosis at 2-3yrs, mutation is 12bp deletion in lig-bind domain of LDL receptor
LDL Receptor knockout mice:
- develops atherosclerosis on normal mouse diets
- worse if feed a high cholesterol diet
Autsosomal Recessive hypercholesterolaemia (ARH)
- Rare
- ARH-1 adaptor protein which binds to both cytosolic tail of LDL receptor and clathrin, required for internalisation of LDL receptor
- In ARH, loss of function of ARH-1, high conc of plasma LDL
PCSK9 mutations
- 2% of cases of dominant FH
- PCSK9 is a protein that which binds to LDL receptor on cell surface. Acts as a chaperone and leads to intracellular degradation of LDL by interfering with their to plasma membrane.
Apolipoprotein B-100 mutations
- Accounts for 5% of cases of autosomal dominant FH
- Dominant genetic disease
- A to G mutation at AA 3500 in LDL receptor binding domain
Treatment of FH by Statins
1) Inhibit cholesterol synthesis by inhibiting (HMG CoA reductase)
2) Decreases the cholesterol content of hepatocytes
3) Activates LDL receptor gene
4) Increases LDL receptor in liver, increases liver uptake
5) Plasma LDL concentrations fall
Not effective in homozygous FH
Lowers LDL considerably by in heterozygous FH
Treatments
LDL Aphresis:
- Used for homozygous FH
- Pass blood through column that absorbs LDL and returns blood to body
- ~ lowers around 60% initially
MTP Inhibitor:
- Reduces LDL cholesterol by 40% in homozygous FH
- Reduces CVD substantially
PCSK9 Antibodies:
- Greater lowering of LDL than statins (2014)
- 60% reduction in LDL in heterozygous FH, 30% reduction in LDL in homozygous FH
