PCSK9 and Cholesterol Homeostasis

The Biology of Cholesterol Synthesis and Metabolism

HMG-COA REDUCTASE IS THE RATE-CONTROLLING ENZYME IN CHOLESTEROL BIOSYNTHESIS.1

Both HMG-CoA reductase and LDLRs are tightly regulated and can be increased or decreased, affecting cholesterol synthesis and homeostasis.2

HMG-CoA Reductase
HMG-CoA
Reductase

Incoming hepatic cholesterol suppresses HMG-CoA reductase, turning off cholesterol synthesis in the cell.1

LDLR
LDLR

In addition, LDLR synthesis is turned off, preventing further entry of LDL and protecting cells against an overaccumulation of cholesterol.1

Recycling of LDLRs enables efficient clearance of plasma LDL particles.2

LDLRs bind to LDL particles and transport them into the hepatocyte. The LDL particles then dissociate from the LDLRs and are broken down. The LDLRs are then free to recycle back to the cell surface and bind to additional LDL particles, clearing them from the blood.2 The ability of LDLRs to be recycled is key to the liver's ability to lower plasma LDL-C levels.

LDLR Recycling

PCSK9 regulates the recycling of LDLRs by targeting the LDLR for degradation3

While HMG-CoA reductase plays a critical role in cholesterol biosynthesis, PCSK9 plays a critical role in cholesterol metabolism.4,5 By promoting LDLR degradation within hepatocytes, PCSK9 reduces the concentration of LDLRs on the hepatocyte surface, resulting in increased plasma LDL-C levels.3

LDLR Recycling
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
PCSK9
PCSK9
Blood
LDL
LDL
LDL
PCSK9
PCSK9
Blood

How are elevated LDL-C levels affecting the patient landscape?

LEARN MORE

CVD = cardiovascular disease; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9.

References

  1. Brown MS, Goldstein JL. Proc Natl Acad Sci USA. 1979;76:3330-3337.
  2. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
  3. Qian Y-W, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498.
  4. Brown MS, Goldstein JL. Science. 1986;232:34-47.
  5. Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177.