Potential role of nonstatin cholesterol lowering agents

Laura Trapani, Marco Segatto, Paolo Ascenzi, Valentina Pallottini

Research output: Contribution to journalArticle

Abstract

Although statins, 3β-hydroxy-3β-methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsic toxicity or to the decrease of HMGR main isoprenoid end products, which are essential compounds for cell viability, is still debated. In addition to HMGR, the key and rate limiting step of cholesterol synthesis, many enzymes are involved in this multi-step pathway whose inhibition could be taken into account for a "nonstatin approach" in the management of hypercholesterolemia. In particular, due to their unique position downstream from HMGR, the inhibition of squalene synthase, farnesyl diphosphate farnesyltransferase (FDFT1), squalene epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase (OSC) should decrease plasma levels of cholesterol without affecting ubiquinone, dolichol, and isoprenoid metabolism. Thus, although FDFT1, SQLE and OSC are little studied, they should be considered as perspective targets for the development of novel drugs against hypercholesterolemia. Here, structurefunction relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin-based therapy.

Original languageEnglish
Pages (from-to)964-971
Number of pages8
JournalIUBMB Life
Volume63
Issue number11
DOIs
Publication statusPublished - Nov 2011

Keywords

  • 3-hydroxy 3-methylglutaryl coenzyme a reductase
  • Cholesterol
  • Hypercholesterolemia
  • Inhibition
  • Oxidosqualene cyclase
  • Squalene epoxidase
  • Squalene synthase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Clinical Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Trapani, L., Segatto, M., Ascenzi, P., & Pallottini, V. (2011). Potential role of nonstatin cholesterol lowering agents. IUBMB Life, 63(11), 964-971. https://doi.org/10.1002/iub.522