Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists?

Gani, Osman A. B. S. M.
January 2008
Cardiovascular Diabetology;2008, Vol. 7, p1
Academic Journal
Background: Peroxisome proliferator-activated receptors (PPARa, PPAR?, and PPARd) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARa agonists which lower lipid level, and glitazones as PPAR? agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARa/? would be a logical approach. But synthetically developed PPARa/? dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases. Presentation of hypothesis: Docosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present hypothesis suggests that the derivatives of these fatty acids are stronger PPAR agonists than the parent compounds. X-ray structures of PPARs indicate that a or � derivatives of fatty acids would fit into PPARa/? binding cavity. Therefore, the derivatives will exhibit stronger affinities and activities than the parent compounds. Testing of the hypothesis: Ligand binding assays and gene transactivation assays should be performed to test the hypothesis. Fluorescence-based methods are advantageous in binding assays, because they were found more suitable for fatty acid binding assays. In transactivation assays, care should be taken to remove contaminants from recombinant proteins. Implications of the hypothesis: Present hypothesis is framed on the basis of molecular structure of natural PPAR agonists. Small structural changes in the molecular structure of fatty acids have a great influence on activating different PPARs. Therefore, this hypothesis bridges the concept of natural PPAR agonists and the use of structural information in designing new drugs against diabetes and metabolic syndrome. The derivatives may also be used as anti-inflammatory and anticancer agents.


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