cDNA cloning, expression and chromosomal localization of two human lysophosphatidic acid acyltransferases.

In this report we describe a pair of human LPAAT isozymes. These isozymes are encoded by distinct genes located on different chromosomes, but share sequence homology, substrate specificity, and intracellular location. The biological value of maintaining the two closely related LPAAT genes in the human genome is not clear. We find that both isozymes are widely expressed, although expression levels do diverge significantly in tissues such as the liver, placenta, testes, and pancreas. We also find that, at least in the artificial system of over-expression in COS7 cells, both isozymes localize to the ER membrane. Thus, distinct tissue-specific or subcellular compartment-specific roles for the two isozymes are not supported by the current experimental evidence. It does remain possible that induction of expression or subcellular translocation of one or the other isozyme may distinguish their functions. A survey of a limited number of acyl CoA substrates indicates that the two isozymes display similar substrate specificities, although slight differences are suggested by the data. However, extensive analysis of both isozymes with multiple substrates in the same assay system will be required to detect physiologically relevant differences in substrate specificity. LPA and PA are central intermediates in phospholipid biogenesis. Furthermore, they have the capacity to mediate signaling both between and within cells. The importance of these mediators is reflected in the growing body of literature dedicated to unraveling the mechanistic basis for their actions. Until recently, the field has been hampered by a dearth of reagents appropriate for the molecular dissection of the LPA and PA metabolic and signaling pathways in eukaryotes. However, the recent cloning of possible LPA receptors will promote further understanding of LPA signaling. Similarly, the recent appearance of LPAAT homologs in the EST database has prompted a flurry of reports describing their characterization. These clones will afford opportunity for defining the function of LPAAT in eukaryotic phospholipid metabolism.