1 Familial Hypercholesterolemia (FH): Premature Cardiovascular Risk Reduction Through Early Action.
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Transcript of 1 Familial Hypercholesterolemia (FH): Premature Cardiovascular Risk Reduction Through Early Action.
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Familial Hypercholesterolemia (FH):
Premature Cardiovascular Risk ReductionThrough Early Action
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3 Genes Affecting LDL Clearance Can Cause FH1000+ Mutations Identified to Date
APOB (6 mutations identified) Codes for production of ligand protein, ApoB, which connects LDL particle to receptor
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
LDL particle
Liver cell
Circulation
LDLR (>1000 mutations) codes for LDL receptor which binds to ApoB on LDL particle inducing endocytosis of LDL
PCSK9 (8 GOF mutations identified to date) codes for PCSK9 enzyme, which degrades the LDL receptor
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Normally, LDL Receptors on hepatocytes help to clear LDL Particles from plasma
LDL particle
Liver cell
Circulation
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
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LDL Receptor (LDLR) Mutations Alter LDL Receptors, Preventing Attachment to Particle
ApoB
LDL particle
LDL receptor
LDL receptor binding site impaired function prevents binding to LDL particle
Normal FH: LDLR-Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
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PCSK9 Mutations Increase Degradation of LDL Receptors, Limiting Binding and Endocytosis
ApoB
PCSK9
LDL particle
LDL receptor
LDL receptorsdegraded at a faster rate by increased PCSK9 activity
Normal FH: PCSK9+Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
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APOB Mutations Alter Shape of Apo B Ligand on LDL, Impeding Ability to “Grab” the LDL Receptor
ApoB
LDL particle
LDL receptor
Normal FH: APOB-
Mutation impairs ApoB-binding ability to LDL
receptor
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.