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New Insights in the Understanding of Cholesterol Metabolism:The Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
in the Regulation of Low-Density Lipoprotein Cholesterol (LDL-C) and LDL
Receptors (LDLRs)
USA-145-100024(1) © 2014 Amgen Inc. All rights reserved. Not for Reproduction.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Pathway
Genetic Variants of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
2
Table of Contents
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Pathway
© 2014 Amgen Inc. All rights reserved. Not for Reproduction.
4
Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis
LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor
1. Steinberg D, et al. Proc Natl Acad Sci. 2009;106:9546-9547. 2. Brown MS, et al. J Lipid Res. 2009;50:S15-S27.
Clathrin-coated vesicleHepatocyte
LDL
LDLR
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Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
LDL-C = low-density lipoprotein cholesterol1. Steinberg D, et al. Proc Natl Acad Sci. 2009;106:9546-9547. 2. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438. 3. Brown MS, et al. Proc Natl Acad Sci. 1979;76:3330-3337.
Increased LDLR surface concentration
Lysosomal degradation
LDLR recycling
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PCSK9 = proprotein convertase subtilisin/kexin type 9
1. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177.3. Brown MS, et al. Proc Natl Acad Sci. 1979;76:3330-3337. 4. Steinberg D, et al. Proc Natl Acad Sci. 2009;106:9546-9547. 5. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438. 6. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
LDLR/PCSK9 routed to lysosome
Lysosomal degradation
PCSK9 secretion
Decreased LDLR surface concentration
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Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels
PCSK9 Gain of Function = Less LDLRs1 PCSK9 Loss of Function = More LDLRs1
1. Steinberg D, et al. PNAS. 2009;106:9546-9547. 2. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272. 3. Benn M, et al. J Am Coll Cardiol. 2010;55:2833-2842.
Mutations in the human PCSK9 gene that lead to a loss of PCSK9 function are found in 1% to 3% of the representative populations2,3
Lysosomal degradation of LDLR
Gain-of-function PCSK9 Loss-of-function PCSK9
Recycling of LDLR
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Gain-of-Function Mutations in PCSK9 Cause Familial Hypercholesterolemia*†
1. Abifadel M, et al. Hum Gen. 2009;30:520-529. 2. Lopez D. Biochem Biophys Acta. 2008;1781:184-191.
3. Cameron J, et al. Hum Mol Genet. 2006;15:1551-1558.
PCSK9 Variant PopulationClinical/Biochemical
Characteristics
D374Y1British, Norwegian
families, 1 Utah family
Tendon xanthomas, severe hypercholesterolemia
S127R1 French, South African, Norwegian families Tendon xanthomas
R218S2 French families Tendon xanthomas, arcus corneae
†For a full list of ADH mutations, please refer to Abifadel reference.
• Associated with:– High serum LDL-C1
– In vitro testing in many identified mutations shows decreased levels of LDLRs3
*Autosomal Dominant Hypercholesterolemia
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Loss-of-Function Mutations in PCSK9 Are Associated With Decreased LDL-C
LOF = loss of functionARIC = Atherosclerosis Risk in Communities (N ~ 4,000); DHS = Dallas Heart Study (N = 3,553); CGPS = Copenhagen General Population Study (N = 26,013)
1. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272. 2. Cohen J, et al. Nat Genet. 2005;37:161-165
3. Benn M, et al. J Am Coll Cardiol. 2010;55:2833-2842. 4. Zhao Z, et al. Am Journal of Hum Gen. 2006;79:514-534.
PCSK9 Variant Population LDL-C
R46L ARIC1, DHS2 ↓ 15%1
Y142X or C679X ARIC1, DHS2 ↓ 28%–40%1
R46L CGPS3 ↓ 11%3
• Heterozygous LOF mutations found in 1% to 3% of representative populations1,3
• Associated with
– Lower serum LDL-C1
• PCSK9 null individual identified (compound heterozygote for two inactivating mutations)
– No detectable circulating PCSK9 with strikingly low LDL-C (14 mg/dL)4
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SREBP = sterol regulatory element-binding protein
1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438. 2. Dubuc G, et al. Arterioscler Thromb Vasc Biol. 2004;24:1454-1459.
LDLR and PCSK9 Expression Are Both Upregulated When Intracellular Cholesterol Levels Are Low
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Expression of PCSK9 Depends on Intracellular Cholesterol Levels
- Cholesterol Depletion*
- Statins↑ SREBP-2 ↑ PCSK9
- Dietary Cholesterol
- Cellular Cholesterol↓ SREBP-2 ↓ PCSK9
*Intracelullar Cholesterol Depletion
1. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:3-23.
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Summary• LDLR and PCSK9 Expression Are Both Regulated by Intracellular
Cholesterol Levels1,2
• Genetic Variants of PCSK9 Support its Role in Regulating LDL Levels2
– Gain-of-function mutations result in increased LDL-C3,4
– Loss-of-function mutations are associated with decreased LDL-C5
1. Dubuc G, et al. Arterioscler Thromb Vasc Biol. 2004;24:1454-1459. 2. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:3-23. 3. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 4. Horton JD, et al. J Lipid Res. 2009;50:S172-S177. 5. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272.