What is the mechanism of action of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)?

Mechanism of Action of PCSK9

PCSK9 primarily functions by binding to LDL receptors on hepatocyte surfaces, promoting their degradation in lysosomes, thereby reducing LDL cholesterol clearance from the bloodstream. 1

Primary Mechanism of PCSK9

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) is a serine protease that plays a crucial role in cholesterol metabolism through the following mechanism:

1. LDLR Binding and Degradation:

   • PCSK9 is secreted by hepatocytes into the circulation
   • It binds to the extracellular EGF-A domain of the LDL receptor (LDLR) on the hepatocyte surface
   • This binding leads to internalization of the LDLR-PCSK9 complex through clathrin-coated pits
   • The complex is directed to lysosomes for degradation rather than being recycled back to the cell surface 1

2. Physiological Consequence:

   • Reduced LDLR recycling to the hepatocyte membrane
   • Decreased availability of LDLRs on the cell surface
   • Higher plasma levels of LDL cholesterol due to reduced clearance 1, 2

Intracellular vs. Extracellular Pathways

PCSK9 can enhance LDLR degradation through two distinct pathways:

1. Extracellular Pathway (Primary mechanism):

   • Secreted PCSK9 binds to LDLR on the cell surface
   • Leads to internalization and lysosomal degradation of the receptor 1

2. Intracellular Pathway:

   • Does not require PCSK9 secretion
   • Evidenced by the S127R PCSK9 gain-of-function variant that causes autosomal dominant hypercholesterolemia without PCSK9 secretion 1

Regulation of PCSK9 Expression

PCSK9 expression is regulated by several factors:

• SREBP2 (Sterol Regulatory Element Binding Transcription Factor 2):

  • Upregulates PCSK9 expression when cellular cholesterol levels are low
  • Interestingly, this is the same transcription factor that upregulates LDLR expression 1

• Inflammatory Mediators:

  • Hepatocyte nuclear factor-1α (HNF-1α), which regulates acute phase pro-inflammatory proteins, induces PCSK9 expression
  • Lipopolysaccharide (LPS) and TNFα can induce hepatic PCSK9 expression 1

PCSK9 Inhibition Mechanism

PCSK9 inhibitors (monoclonal antibodies) work through the following mechanism:

1. Binding to Circulating PCSK9:

   • Monoclonal antibodies (evolocumab, alirocumab) bind to free circulating PCSK9
   • This prevents PCSK9 from binding to LDLR 2, 3

2. Increased LDLR Availability:

   • Prevents LDLR degradation
   • Enhances LDLR recycling to the cell surface
   • Increases the number of LDLRs available to clear LDL from the blood 2

3. Lipid-Lowering Effects:

   • Reduces LDL cholesterol levels
   • Also reduces triglycerides, total cholesterol, and Lp(a)
   • Increases HDL and ApoA1 levels 1

Beyond Lipid Metabolism: Additional PCSK9 Functions

PCSK9 has several functions beyond regulating LDL metabolism:

1. Pro-inflammatory Effects:

   • Enhances expression of pro-inflammatory markers
   • May contribute to inflammation within the vascular wall 1, 4

2. Role in Sepsis:

   • LPS circulates bound to LDL
   • PCSK9 inhibition may increase LPS clearance through increased LDLR expression
   • Humans with PCSK9 loss-of-function variants show improved clinical outcomes during septic shock
   • Enhanced plasma PCSK9 levels during sepsis are associated with multiple organ failure 1

3. Cardiovascular Effects:

   • May promote apoptosis, pyroptosis, and ferroptosis of cardiomyocytes
   • Potentially involved in heart failure development and progression 4

Clinical Implications

Understanding PCSK9's mechanism of action has led to the development of effective therapeutic strategies:

1. Monoclonal Antibodies:

   • Evolocumab and alirocumab block the extracellular PCSK9 pathway
   • Reduce LDL-C by up to 60-70% when used alone or in combination with statins 2, 3

2. Complementary Mechanisms:

   • PCSK9 inhibitors, statins, and ezetimibe exhibit complementary mechanisms of action:
     • Statins inhibit HMG-CoA reductase, reducing hepatic cholesterol synthesis
     • Ezetimibe inhibits intestinal cholesterol absorption through NPC1L1
     • PCSK9 inhibitors prevent LDLR degradation 1

Note: While statins upregulate LDLR expression, they also enhance PCSK9 synthesis, which partially blunts their LDL-C-lowering effectiveness. This explains why combining statins with PCSK9 inhibitors produces synergistic effects on LDL-C reduction. 5

Human Genetics

PCSK9 genetic variants provide strong evidence for its role in cholesterol metabolism:

• Loss-of-function mutations result in lifelong low LDL-C levels and reduced cardiovascular risk
• Gain-of-function mutations lead to autosomal dominant hypercholesterolemia 5

This genetic evidence provided the rationale for developing PCSK9 inhibitors as therapeutic agents for hypercholesterolemia.