AOAH

Acyloxyacyl hydrolase, also known as AOAH, is a eukaryotic protein encoded by the AOAH gene.^[5] AOAH is produced by macrophages (including Kupffer cells and microglia), dendritic cells (especially in the colon), NK cells, ILC1 cells, neutrophils and renal proximal tubule cells.^[6]

AOAH
Identifiers
Aliases	AOAH, acyloxyacyl hydrolase
External IDs	OMIM: 102593; MGI: 1350928; HomoloGene: 1238; GeneCards: AOAH; OMA:AOAH - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p14.2 Start 36,512,941 bp[1] End 36,724,549 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13|13 A2 Start 20,978,283 bp[2] End 21,220,787 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte monocyte blood spleen rectum pancreatic ductal cell appendix mucosa of transverse colon bone marrow cell lymph node Top expressed in granulocyte right kidney stroma of bone marrow proximal tubule human kidney blood blastocyst calvaria gastrula zygote More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hydrolase activity hydrolase activity, acting on ester bonds calcium ion binding acyloxyacyl hydrolase activity metal ion binding Cellular component extracellular region cytoplasmic vesicle Biological process fatty acid metabolic process lipopolysaccharide catabolic process lipid metabolism Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 313 27052 Ensembl ENSG00000136250 ENSMUSG00000021322 UniProt P28039 O35298 RefSeq (mRNA) NM_001177506 NM_001177507 NM_001637 NM_001281854 NM_012054 RefSeq (protein) NP_001170977 NP_001170978 NP_001628 NP_001268783 NP_036184 Location (UCSC) Chr 7: 36.51 – 36.72 Mb Chr 13: 20.98 – 21.22 Mb PubMed search [3] [4]
Wikidata
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Species distribution

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]

Structure

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]

Function

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]

Animal studies

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]