br Medium and long chain fatty

Medium- and long-chain fatty INCB 018424 receptors
Clinical studies of ω3 fatty acids Clinical studies have established that dietary intake of ω3 fatty acids should be around 4g/day for treating very high triglyceride levels (≥5.7mmol/L) [36]. Low-dose supplementation with EPA + DHA (400mg/day) or ALA (2g/day) did not significantly reduce the rate of major cardiovascular events among patients who had a myocardial infarction, and who were receiving state-of-the-art antihypertensive, antithrombotic and lipid-modifying therapy [37]. The dose of ω3 fatty acids used in clinical trials varies widely from approximately 400mg to 16.2g per day, and the most beneficial dose in humans is still under investigation 26, 28, 29, 38. The most commonly reported adverse effect of ω3 fish oil supplements is a fishy aftertaste and eructation, but several other side effects have also been reported, including nausea and gastric bleeding 11, 25, 39, 40. Among the more serious side effects, one study suggested that ω3 supplements could result in a slightly higher risk of hemorrhagic stroke [41]. Consumption of high levels of fish oil can also result in hypervitaminosis, a condition associated with high levels of vitamins – A and D – that are usually added to the fish oils [42]. Clinically, low doses of ω3 fatty acids are largely ineffective, even in the context of combination therapy. Should fish oils prove impractical as a therapeutic agent, the identification of the GPR120 receptor suggests that synthetic DHA + EPA mimetics could be developed that might provide the same and potentially greater anti-inflammatory effects. Synthetic agonists have certainly been more potent than endogenous ligands, as demonstrated by synthetic agonists of liver X receptors [43] and farnesoid X receptors [44]. A recent report suggested potential synthetic agonists of GPR120 based on molecular modeling [45] that could be further explored to obtain clinical benefits.
Short-chain fatty acid receptors GPR43 and GPR41 are both activated by short-chain FFAs such as formate, acetate, propionate, butyrate and pentanoate 59, 67, 68. GPR43 and GPR41 differ in their specificity for ligands with different length carbon chains (Table 1). GPR41 is activated equally by propionate, butyrate and pentanoate, whereas GPR43 prefers propionate to other short-chain FFAs 67, 68.
Concluding remarks Fatty acids are not only essential nutrients but also play important roles as endocrine regulators of lipid and carbohydrate metabolism through the activation of their cognate GPCRs. FFARs play significant roles in nutritional regulation by sensing both long- and short-chain fatty acids. The deorphanization of more GPCRs is likely to identify additional receptors of endogenous signaling molecules, including FFAs. Our recent study established GPR120 as a physiological receptor of ω3 fatty acids in macrophages and adipocytes that mediates potent anti-inflammatory and insulin-sensitizing effects. Targeting fatty acid-sensing GPCRs to ameliorate inflammatory disease is an exciting and growing area, and many clinical trials are currently underway to explore the beneficial anti-inflammatory therapeutic effects of ω3 fatty acids in a broad spectrum of disease. Hippocrates in his wisdom clearly ‘nailed it’ when he said almost 2500 years ago: “Let food be your medicine and let medicine be your food. Only nature heals, provided it is given the opportunity” [87]. In the context of the global diabetes and inflammatory disease epidemic, we should have heeded his words sooner.
Acknowledgment
Introduction G protein-coupled receptors (GPCRs) represent the largest superfamily of integral membrane proteins. The human genome encodes approximately 400 nonodorant GPCRs (Fredriksson and Schioth, 2005, Takeda et al., 2002, Vassilatis et al., 2003), which are activated by extremely diverse stimuli, including hormones, neurotransmitters, Ca2+ ions, lipids, photons, and peptides (Lagerstrom and Schioth, 2008, Perez, 2003, Pierce et al., 2002). The ability of GPCRs to act as signal transducers, binding an extracellular ligand in order to produce an intracellular biological response, has made these receptors the most historically successful drug targets (Hopkins & Groom, 2002). Indeed, recent estimates suggest that approximately 30% of all currently used pharmaceutical agents target GPCRs (Fredriksson and Schioth, 2005, Jacoby et al., 2006, Summers, 2010). However, despite their success as drug targets, only approximately 30 of the more than 400 known nonodorant GPCRs are currently targeted by therapeutics (Tyndall & Sandilya, 2005), suggesting that there are still many additional GPCR drug targets yet to be exploited.