AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice.

摘要: Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation FAHFAs remains pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS–based lipidomics analyses, activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) androgen-dependent TFPI-regulating (ADTRP), two threonine hydrolases, control levels in vivo both genetic pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or AIG1 (DKO) had higher concentrations particularly isomers ester bond at 9th carbon due to decreased activity. The other lipid classes were unaltered indicating specifically hydrolyze FAHFAs. Complementing these studies, also identified dual AIG1/ADTRP inhibitor, ABD-110207, which is active vivo. Acute treatment WT ABD-110207 resulted elevated levels, further supporting notion activity levels. loss did not mimic changes associated pharmacologically administered on extent upregulation glucose tolerance, insulin sensitivity mice, therapeutic strategies should weigh more administration. Together, findings identify as first hydrolases provide critical chemical tools for characterization enzymes unravel their physiological functions roles health disease.