Therapeutic Targets

Lipid-Lowering PCSK9 Inhibitors

The liver removes LDL cholesterol (LDL-C) from the bloodstream via LDL receptors (LDLR). By binding and internalizing LDL particles, LDLR ensures proper metabolism of lipids.  

There’s a sinister antagonist that lingers and limits this process. PCSK9 (proprotein convertase subtilisin/kexin type 9) is a small protein that binds LDLR and promotes its destruction. As a result, serum LDL-C levels remain elevated.  PCSK9 inhibitors represent a unique and promising class of therapeutics for the treatment of hypercholesterolemia.1-8   

How PCSK9 Interferes with Lipid Lowering

To leave the bloodstream, LDL particles must enter liver cells by attaching to LDLR on cell membranes.  The complex is then engulfed into a vesicle called an endosome, where LDLR undergoes a conformational change that releases the LDL-C, which is subsequently metabolized.  LDLR remains intact, returning to the membrane to repeat the process.9-12

When PCSK9 is present, it binds to LDLR (refer to the diagram above).  Instead of entering an endosome for selective detachment, it undergoes complete degradation in a vesicle called a lysosome. Destruction of LDLR precludes its return to the membrane.5,7,8,12 Consequently, fewer LDLR receptors are available to keep serum LDL-C low.

Genetic Mutations in the PCSK9 Gene

Gain of function mutations are associated with familial hypercholesterolemia (FH).1-4,9.  Conversely, loss-of-function mutations are associated with a 28-44% reduction in plasma LDL-C levels and up to an 88% reduction in cardiovascular risk.2-3 

Pharmaceutical Inhibitors

Parenteral PCSK9 inhibitors are highly effective lipid-lowering agents.  However, attempts to develop oral drugs have been unsuccessful.  Two monoclonal antibodies, evolocumab (Repatha®) and alirocumab (Praluent®), are FDA approved for the treatment of FH.12 Small interfering RNAs (siRNAs), vaccines and antisense oligonucleotides (ASOs) also reduce plasma LDL-C with profound efficacy. The annual cost of current therapies to the patient may exceed $14,000 per year.13 Consequently, there is considerable interest in affordable adjuncts and alternatives.

Natural Product Inhibitors

Berberine is a transcriptional inhibitor of PCSK9 that augments LDLR stability and density.12,14,15 Clinical trials have offered ample support for its antihyperlipidemic efficacy.12,14,15  Due to low potency and poor absorption, berberine is much less effective than pharmaceutical inhibitors, but divergent and complementary mechanisms support its promise as an adjunct.12  Its modes of action extend beyond lipid trafficking, with emerging evidence highlighting the microbiome as a conduit for its cardiometabolic benefits.  

Omega-3 fatty acids suppress of hepatic PCSK9 expression. Human clinical data support reductions in circulating PCSK9 levels (e.g. an 11.4% decrease) with supplementation.18,19

Curcumin suppresses PCSK9 expression in cell culture models, but clinical data are needed to confirm this effect is relevant in vivo. A high oral dose would be required to achieve an effective inhibitory concentration (10 μM).12 

Polydatin (resveratrol-3-O-β-mono-d-glucoside), also known as piceid, is a resveratrol glycoside that inhibits PCSK9 expression and interaction with LDLR.12. The research on polydatin remains preliminary.

Quercetin-3-O-beta-D-glucoside (Q3G; Isoquercetin) is another transcriptional inhibitor, reducing mRNA expression of PCSK9 by 20-30% while increasing LDLR mRNA and protein expression by 60% and 300-400%, respectively, in human hepatocytes.17

The foregoing natural inhibitors are potentially useful for lifestyle-related, uncomplicated hyperlipidemias. Because they are far less potent and orally less bioavailable than current pharmaceutical inhibitors, they should not be considered as primary monotherapies in FH or severe hyperlipidemia. More research is needed to characterize clinical efficacy in combination with lipid-lowering drugs.

References

  1. Abifadel M, et al (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 34 (2): 154–6.
  2. Cohen JC, et al (2006). Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New Eng J Med. 354 (12): 1264–72.
  3. Cohen J, et al (2005). Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 37 (2): 161–5.
  4. Kathiresan S (2008). A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. New Eng J Med. 358 (21): 2299–300.
  5. Zhang DW, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 282 (25): 18602–18612.
  6. Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia. Annual Review of Pharmacology and Toxicology (2014) 54: 273–93.
  7. Schulz R, Schlüter KD, Laufs U (March 2015). “Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9)”. Basic Research in Cardiology. 110 (2): 4. 
  8. Cariou B, Langhi C, Le Bras M, et al. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets”. Nutrition & Metabolism. 10 (1): 4.
  9. Mega JL, et al. (2015). Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials”. Lancet. 385 (9984): 2264–71.
  10. Tsouka AN, et al.  Pharmacology of PCSK9 Inhibitors: Current Status and Future Perspectives. Curr Pharm Des. 2018;24(31):3622-3633.   
  11. Crossey E, et al. (2015). A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. 33 (43): 5747–55.
  12. Momtazi AA, Banach M, Pirro M, Katsiki N, Sahebkar A. Regulation of PCSK9 by nutraceuticals. Pharmacol Res. 2017 Jun;120:157-169.
  13. Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD, Tice JA, Guzman D, Bibbins-Domingo K. Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease. JAMA 316(7) (2016) 743-753.
  14. W. Kong, J. Wei, P. Abidi, M. Lin, S. Inaba, C. Li, Y. Wang, Z. Wang, S. Si, H. Pan, Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins, Nature medicine 10(12) (2004) 1344-1351.
  15. P. Abidi, Y. Zhou, J.-D. Jiang, J. Liu, Extracellular signal-regulated kinase–dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine, Arteriosclerosis, Thrombosis, and Vascular Biology 25(10) (2005) 2170-2176.
  16. H. Li, B. Dong, S.W. Park, H.-S. Lee, W. Chen, J. Liu, Hepatocyte nuclear factor 1α plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine, Journal of Biological Chemistry 284(42) (2009) 28885-28895.
  17. M. Mbikay, F. Sirois, S. Simoes, J. Mayne, M. Chrétien, Quercetin‐3‐glucoside increases low‐density lipoprotein receptor (LDLR) expression, attenuates proprotein convertase subtilisin/kexin 9 (PCSK9) secretion, and stimulates LDL uptake by Huh7 human hepatocytes in culture, FEBS open bio 4(1) (2014) 755-762.
  18. S. Kourimate, C. Le May, C. Langhi, A.L. Jarnoux, K. Ouguerram, Y. Zaïr, P. Nguyen, M. Krempf, B. Cariou, P. Costet, Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9, Journal of Biological Chemistry 283(15) (2008) 9666-9673.
  19. G. Lambert, A.-L. Jarnoux, T. Pineau, O. Pape, M. Chetiveaux, C. Laboisse, M. Krempf, P. Costet, Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor, Endocrinology 147(10) (2006) 4985-4995.

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