Characterization of the Rodent Genes for Arylacetamide Deacetylase, a Putative Microsomal Lipase, and Evidence for Transcriptional Regulation

Jeffrey I. Trickett, Dilip D. Patel, Brian L. Knight, E. David Saggerson, Geoffrey F. Gibbons, Richard J. Pease
2001 Journal of Biological Chemistry  
In the current study, we have determined the cDNA and the genomic sequences of the arylacetamide deacetylase (AADA) gene in mice and rats. The AADA genes in the rat and mouse consist of five exons and have 2.4 kilobases of homologous promoter sequence upstream of the initiating ATG codon. AADA mRNA is expressed in hepatocytes, intestinal mucosal cells (probably enterocytes), the pancreas and also the adrenal gland. In mice, there is a diurnal rhythm in hepatic AADA mRNA concentration, with a
more » ... ntration, with a maximum 10 h into the light (post-absorptive) phase. This diurnal regulation is attenuated in peroxisome proliferator-activated receptor ␣ knockout mice. Intestinal but not hepatic AADA mRNA was increased following oral administration of the fibrate, Wy-14,643. The homology of AADA with hormone-sensitive lipase and the tissue distribution of AADA are consistent with the view that AADA plays a role in promoting the mobilization of lipids from intracellular stores and in the liver for assembling VLDL. This hypothesis is supported by parallel changes in AADA gene expression in animals with insulin-deficient diabetes and following treatment with orotic acid. It is now clear that one or more lipases must play a role in the secretion of very low density lipoprotein triacylglycerol (VLDL-TAG) 1 from the liver. A large proportion of the VLDL-TAG secreted is derived from the cytosolic TAG storage pool in hepatocytes (1). This pool enables short term storage of TAG in the immediate post-prandial period and its subsequent secretion as VLDL-TAG when the level of circulating chylomicrons falls. Thus the store may act as a buffer to prevent postprandial hyperlipidemia (for review see Ref. 2). For VLDL assembly, the stored TAG undergoes intracellular lipolysis either to glycerol plus fatty acids (3) or to mono-plus diacylglycerol (4) followed by re-esterification to TAG (3, 4) . In addition to the mobilization of stored TAG, there is also evidence that the lipids associated with nascent VLDL in the endoplasmic reticulum lumen undergo remodeling prior to secretion (5), and this may also involve the action of the same or of a distinct lipase. The identities of the relevant lipases have not been established. have proposed that both triglyceride hydrolase (TGH, an endoplasmic reticulum luminal carboxylesterase) and other lipases together play a role in the mobilization of stored lipid for secretion. Of particular interest, they have shown that TGH is not expressed during the suckling period of life and have suggested that this results in decreased VLDL secretion during this phase (7) . Arylacetamide deacetylase (AADA) is a 45-kDa esterase with an uncleaved amino-terminal signal anchor sequence. The enzyme was purified from human liver (9) and the human cDNA cloned by Probst et al. (10) during studies of carcinogen metabolism
doi:10.1074/jbc.m101764200 pmid:11481320 fatcat:3n7dluja3badhbplvyi73lfxri