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J Biol Chem. 2020 Mar 9. pii: jbc.RA119.012145. doi: 10.1074/jbc.RA119.012145. [Epub ahead of print]

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

Author information

1
Salk Institute for Biological Studies, United States.
2
The Scripps Research Institute, United States.
3
The Scripps Research institute, United States.
4
Salk Institute.
5
MASS, Salk Institute for Biological Studies, United States.
6
Lundbeck La Jolla Research Center, United States.
7
Cell Biology, The Scripps Research Institute, United States.
8
Scripps Research Institute, United States.

Abstract

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

KEYWORDS:

androgen induced gene 1 (AIG1); androgen-dependent TFPI-regulating protein (ADTRP); diabetes; enzyme inhibitor; fatty acid ester of hydroxy fatty acid (FAHFA); glucose metabolism; lipid ester; lipid signaling; metabolism; threonine hydrolase

PMID:
32152231
DOI:
10.1074/jbc.RA119.012145
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