AOAH

The AOAH gene has been found in many invertebrates and in all vertebrates studied to date except fish. Although mice have other well-established mechanisms for preventing LPS signaling, none of these has prevented long-term persistence of stimulatory LPS in animals that lack AOAH.^[7][8]

The enzyme's 2 disulfide-linked subunits are encoded by a single mRNA. The smaller subunit is a member of the saposin-like (SAPLIP) protein family and the larger subunit, which contains the active site serine, is a GDSL lipase. The enzyme's 3D structure and catalytic mechanism were reported by Gorelik et al.^[9]

Acyloxyacyl hydrolase (AOAH) is a lipase that selectively releases the secondary (acyloxyacyl-linked) fatty acyl chains from the hexaacyl lipid A moiety found in many bacterial lipopolysaccharides (LPSs, also called endotoxins).^[5][6] The resulting tetraacyl LPS is non-stimulatory and can be a potent inhibitor of LPS sensing via the MD-2--Toll-like Receptor 4 (TLR4). The enzyme's other known substrates include bacterial lipopeptides and several host glycerolipids, including lyso-and oxidized phospholipids.^[6][10]

Absence of the enzyme in genetically engineered mice has been associated with distinctive phenotypes. AOAH-deficient animals are unable to inactivate even small amounts of LPS in most tissues; the LPS remains bioactive and may pass from cell to cell in vivo for many weeks. The LPS-injected mice develop strikingly high titers of polyclonal antibodies, prolonged hepatomegaly, and innate immune "tolerance" that results in slow and inadequate responses to a bacterial challenge. Absence of the enzyme renders mice more likely to develop severe lung injury and die if they are challenged with intratracheal LPS, Gram-negative bacteria, or acid (AOAH may also inactivate oxidized phospholipids).^[10][11] Other studies have found that AOAH reduces the stimulatory potency of LPS that translocates from the gastrointestinal tract to the liver and other organs.^[12] AOAH may also prevent LPS-induced arterial foam cell formation in vivo.^[13]