potential as therapeutic targets for various metabolic and inflammatory disorders, including obesity, type 2 diabetes, atherosclerosis, cardiovascular diseases, ulcerative colitis, Crohn’s disease and irritable bowel disease. 123 13 Page 16 of 20 Basic Res Cardiol 112:13 OR51E1 is the highest expressed orphan MCFA-sensing receptor according to our transcriptome data. The ligand spectrum of the free fatty acid receptors known to date is only partially overlapping with that of OR51E1. Among the FFAR family, FFAR1 and FFAR4 are classified as medium- to long-chain fatty acid-activated receptors . FFAR2 and FFAR3 respond to short-chain fatty acids that have fewer than five carbon atoms. Nonetheless, a potential role of FFAR4 in the cardioprotective effect of eicosapentaenoic acid was recently described. Only the free fatty acid receptor GPR84 is activated by nonanoic acid, whereby nonanoic acid displays the weakest ligand. According to our transcriptome analysis and as previously described, all five receptors are not or only very weakly expressed on mRNA level in the human ventricular myocardium. Because the OR51E1 antagonist and knockdown experiments abolished the nonanoic acid-induced effect completely, we propose that the observed action of MCFA on cardiomyocytes is primarily mediated by OR51E1, but the involvement of other FFARs in sensing OR51E1-activating MCFA cannot be fully excluded in an in vivo situation. Effects of MCFA on cardiac function were previously reviewed by Francois Labarthe and colleagues. The authors suggested that MCFA not only provide a buy Relebactam highly efficient source of energy production as contrary to LCFA they enter the cells by free diffusion and are preferentially directed toward oxidation rather than storage. MCFA also may positively modulate cardiac disease progression 
when considering the heart’s energy status and contractile dysfunction. In animal heart models, MCFA were reported to improve diabetic cardiomyopathy, prevent cardiac hypertrophy and recover metabolism and contractile function after transient ischemia. The role of OR51E1 in MCFA-mediated benefits for cardiac function or disease progression remains elusive but would be interesting to examine in further studies. Moreover, polyunsaturated fatty acids, such as arachidonic and eicosapentaenoic acid, have been shown to affect Ca2 handling of cardiomyocytes in vitro. PUFAs induce negative inotropy and inhibit Ca2 transients, which leads to the consideration of PUFAs as antiarrhythmic agents. Furthermore, arachidonic acid was described to counteract b-adrenergic receptor-induced stimulation and was consequently considered to perform a cardiac protective function. The results of this study indicate at negative inotropic effects of OR51E1 activation in vivo, however, do not allow for straightforward interpretation of a clinical relevance as further preclinical and eventually clinical evaluation are required to qualify OR51E1 as a cardiovascular drug target. Preclinical testing in animal models should be conducted in future studies. Interestingly, the OR51E1 and OR51E2 mouse orthologs were found to be expressed in the carotid body and the OR51E2 mouse ortholog, namely Olfr78, acts as a hypoxia sensor. A decreasing oxygen level leads to the production of lactate that in turn affects the breathing circulation via Olfr78. This finding represents an alternative physiological function of an OR by detecting PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19793655 an endogenous ligand. In the human heart, OR51E1 may act as die
