PPARs and their metabolic modulation: New mechanisms for transcriptional regulation?

W. Ahmed, O. Ziouzenkova, J. Brown, P. Devchand, S. Francis, M. Kadakia, T. Kanda, G. Orasanu, M. Sharlach, F. Zandbergen, J. Plutzky

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptors (PPARs) as ligand-activated nuclear receptors involved in the transcriptional regulation of lipid metabolism, energy balance, inflammation, and atherosclerosis are at the intersection of key pathways involved in the pathogenesis of diabetes and cardiovascular disease. Synthetic PPAR agonists like fibrates (PPAR-α) and thiazolidinediones (PPAR-γ) are in therapeutic use to treat dyslipidaemia and diabetes. Despite strong encouraging in vitro, animal model, and human surrogate marker studies with these agents, recent prospective clinical cardiovascular trials have yielded mixed results, perhaps explained by concomitant drug use, study design, or a lack of efficacy of these agents on cardiovascular disease (independent of their current metabolic indications). The use of PPAR agents has also been limited by untoward effects. An alternative strategy to PPAR therapeutics is better understanding PPAR biology, the nature of natural PPAR agonists, and how these molecules are generated. Such insight might also provide valuable information about pathways that protect against the metabolic problems for which PPAR agents are currently indicated. This approach underscores the important distinction between the effects of synthetic PPAR agonists and the unequivocal biologic role of PPARs as key transcriptional regulators of metabolic and inflammatory pathways relevant to diabetes and atherosclerosis.

Original languageEnglish
Pages (from-to)184-198
Number of pages15
JournalJournal of Internal Medicine
Volume262
Issue number2
DOIs
Publication statusPublished - 2007 Aug

Keywords

  • Fatty acids
  • Fibrates
  • Lipases
  • Lipoproteins
  • PPARs
  • Thiazolidinediones

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Ahmed, W., Ziouzenkova, O., Brown, J., Devchand, P., Francis, S., Kadakia, M., Kanda, T., Orasanu, G., Sharlach, M., Zandbergen, F., & Plutzky, J. (2007). PPARs and their metabolic modulation: New mechanisms for transcriptional regulation? Journal of Internal Medicine, 262(2), 184-198. https://doi.org/10.1111/j.1365-2796.2007.01825.x