UC San Diego

Fats or lipids are thought to be deleterious to human health, but recent research has begun to identify beneficial roles for these molecules. Branched fatty acid esters of hydroxy fatty acids, named FAHFAs, are a newly discovered group of lipids that are produced in mammalian tissues. Administration of purified FAHFAs to mice reverses diabetes and reduces inflammation, indicating that raising the levels of these lipids in vivo would be of therapeutic benefit. Indeed, analysis of FAHFA levels in humans revealed that people with type 2 diabetes had lower FAHFA levels than healthy individuals. One approach to raising FAHFA levels would be to inhibit the proteins that are responsible for degrading these lipids in vivo. As newly discovered lipids there are many questions that remain about these molecules, their regulation, structure, and biological roles. Here we make progress on all these fronts. First, we report the identification and characterization of the first FAHFA hydrolases: carboxyl ester lipase (CEL), androgen-induced gene 1 (AIG1) protein, and androgen-dependent TFPI regulating protein (ADTRP). We have developed inhibitors of these enzymes and hypothesize that by inhibiting these enzymes, we can increase FAHFA levels which will result in reduced inflammation and better metabolic parameters. Second, we have characterized the structure and biological activity of a novel FAHFA family discovered in oats called linoleic acid esters of hydroxy linoleic acid (LAHLAs). LAHLAs are more potent than previously characterized FAHFAs in similar assays, and regulate key genes involved in inflammation. These findings open up the possibility of using LAHLAs or LAHLA analogs to modulate the immune system. In addition to these major findings, we have also refined the structure of FAHFAs through the identification of the stereochemistry of these lipids in cells and tissues of mice. The identification of a preferred stereoisomer in vivo indicates that FAHFAs are produced by unidentified enzymes because non-enzymatic production of the hydroxy fatty acid would result a racemic mixture of FAHFAs. Finally, we optimized the methods for FAHFA analysis, which will increase the rate that labs can study FAHFAs and open up the possibility to analyze hundreds of samples for clinical applications.