Metabolism and biological functions of 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid

12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) is a 17-carbon hydroxy fatty acid that is biosynthesized either by enzymatic pathways, like thromboxane synthase (TXAS) and cytochrome P450 or a non-enzymatic pathway. TXAS catalyzes the isomerization reaction from PGH₂ to 12-HHT, malondialdehyde, and TXA₂ at a ratio of 1:1:1. Furthermore, 12-HHT has been considered as a mere byproduct of TXA₂ biosynthesis, and its biological function has long been uncertain. BLT2 was initially identified as a low-affinity leukotriene B₄ (LTB₄) receptor, which is also activated by various hydroxy-eicosatetraenoic acids (HETEs), suggesting that BLT2 may be activated by other endogenous ligands apart from LTB₄ and HETEs. By unbiased ligand screening using crude lipids from rat organs, 12-HHT has been identified as an endogenous agonist for BLT2. The 12-HHT-BLT2 axis induces mast cell migration and contributes to allergic inflammation. BLT2 is also expressed in epithelial cells of the small intestine and skin in mice and contributes to in vivo epithelial barrier functions.