FAHFAs

Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) are a new class of endogenous lipids with anti-diabetic and anti-inflammatory activity. FAHFA levels correlate with insulin resistance and the propensity to develop diabetes, with insulin-resistant people having lower FAHFA levels. Further, administration of FAHFAs to obese insulin-resistant mice improves glucose tolerance, inhibits adipose tissue inflammation, and enhances insulin sensitivity. Although FAHFAs have been shown to improve metabolic parameters and limit inflammation in different labs, the structure-activity relationship and the mechanism by which FAHFAs regulate these processes is not well understood. Only a very small subset of FAHFAs have been studied to date and the systematic combinations of hydroxy fatty acids with fatty acids in nature provides a very large number of these endogenous compounds (>1000) that are of unknown biological function. For example the combination of hydroxypalmitic acid and hydroxypalmitoleic regioisomers with only four fatty acids represents 48 FAHFAs (96 if single enantiomers are considered) that have not been studied.

The most studied FAHFAs are relatively easily prepared and include 9-PAHSA, 13-LAHLA, and 13-DHAHLA. Syntheses of FAHFAs have largely been developed for saturated derivatives or use the readily accessible starting material. Synthetic routes to these derivatives benefit from less functional group incompatibility and more options for starting material selection. Unsaturated FAHFAs, particularly in the hydroxy fatty acid portion, have been studied to a lesser extent than the saturated FAHFAs as a direct result of the difficulties in accessing material for testing. Given the improved potencies of unsaturated FAHFAs relative to saturated derivatives there is a clear need to access these compounds for further study, such as 17-DHAHDHA.