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Cholesterol synthesis and regulation

LDLR recycling and cholesterol homeostasis1-4

Cholesterol plays an important role in many physiological functions, but it can become harmful at excessive plasma levels and it’s a key risk factor for CV events. Cholesterol is mainly produced by the liver, which also regulates plasma LDL through LDL-receptor (LDLR)-mediated clearance.

LDL Circulation Icon

LDL Circulation4

Dietary cholesterol and cholesterol produced de-novo are transported in the blood by LDL and other apolipoprotein B (apoB)-containing lipoproteins.

Liver Icon

LDL Uptake in the Liver1,4

ApoB-containing lipoproteins bind to LDLRs on the surface of hepatic cells and receptor-bound lipoproteins are internalized through endocytosis (the cell absorbs LDL).

LDL Clearance Icon

LDL Clearance1

Internalized LDLRs dissociate from apoB-containing lipoproteins and are recycled back to the cell surface while LDL is hydrolyzed in lysosomes.

Recycling of LDLRs Enables Efficient Clearance of LDL Particles From the Blood1,5,6

An estimated 70% of systemic LDL-C is cleared from the circulation through the hepatic cell LDLRs. Complex feedback loops maintain constant levels of intracellular LDL-C, despite changes in circulating LDL-C levels.

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PCSK9 plays an important role in LDL regulation1,7

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the mammalian proprotein convertase family of secretory serine endoproteases. PCSK9 functions as a molecular chaperone, binding to an LDLR/LDL-C complex and targeting it for lysosomal degradation once the LDLR/LDL-C complex has been pulled into the hepatic cell. This helps achieve LDL-C homeostasis and controls the amount of LDLRs on the hepatic cell surface. PCSK9 directs the degradation of LDLR via two separate pathways:

  • Intracellular pathway: nascent PCSK9 binds to LDLR and directs it from the trans-Golgi to the lysosome
  • Extracellular pathway: secreted PCSK9 binds to LDLR and directs internalized LDLR for degradation by the lysosome, inhibiting further LDLR recycling and LDL-C clearance

See how PCSK9 supports cholesterol homeostasis and download the resource below.

Download Booklet

Studies of genetic variations in PCSK9 demonstrate its impact on LDL levels

Gain-of-function (GOF) mutations5

result in fewer LDLRs, which causes high serum LDL-C (associated with familial hypercholesterolemia [FH]).

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Loss-of-function (LOF) mutations5

result in more LDLRs, which is associated with lower serum LDL-C.

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Familial hypercholesterolemia

FH is an autosomal co-dominant disorder most commonly caused by the following mutations:2,8

dna
  • LOF-mutations in the LDLR genethat affect binding to LDL particles and decrease LDLR function
  • LOF-mutations in the apoB genethat reduce the ability of apoB-containing lipoproteins to bind to the LDLR
  • GOF-mutations in the PCSK9 genethat result in reduced levels of LDLR in the liver8

If left untreated, people with FH reach elevated levels of LDL-C and develop CHD early in life.9

Heterozygous FH (HeFH) affects between 1 in 200 to 250 people and is characterized by marked hyperlipidemia (LDL-C ≥ 190 mg/dL), premature development of atherosclerosis, and coronary artery disease.9,10

Percentage of people with untreated HeFH who will experience a coronary event before the age of 6011

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~50% MEN

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~30% WOMEN

Homozygous FH (HoFH) affects 1 in 1,000,000 people, is characterized by LDL-C > 500 mg/dL, and presents a much more severe phenotype than people with HeFH. People with HoFH have plasma LDL-C 2x higher than HeFH, which puts them at risk of premature development of atherosclerosis and coronary artery disease.2,9,12

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On average, people with FH who do not receive treatment reach the cumulative LDL-C burden sufficient for the development of CHD 20 years earlier than people without FH.9

Educational Resources

See interactive educational resources on ASCVD

Access Resources

CHD = coronary heart disease; FH = familial hypercholesterolemia.

  • References

    1. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
    2. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38:2459-2472.
    3. Turley SD. Cholesterol metabolism and therapeutic targets: rationale for targeting multiple metabolic pathways. Clin Cardiol. 2004;27:III-16–III-21.
    4. Lagor WR, Millar JS. Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease. J Receptor Ligand Channel Res. 2010;3:1-14.
    5. Steinberg D, Witzum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546-9547.
    6. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111:1795-1803.
    7. Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol. 2014;25:387-393.
    8. Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J Lipid Res. 2008;49:1595-1599.
    9. Nordestgaard BG, Chapman JM, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34:3478-3490.
    10. Bouhairie VE, Goldberg AC. Familial Hypercholesterolemia. Cardiol Clin. 2015;33:169-179.
    11. Sharifi M, Rakhit RD, Humphries SE, Nair D. Cardiovascular risk stratification in familial hypercholesterolaemia. Heart. 2016;102:1003-1008.
    12. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146-2157.