Comparative studies of adipose triglyceride lipase genes and proteins: an ancient gene in vertebrate evolution

Abstract

At least eight families of mammalian patatin-like phospholipase domain-containing proteins (EC 3.1.1.3) catalyze the hydrolysis of triglycerides, including adipose triglyceride lipase (ATGL), which functions in triglyceride lipase metabolism in the body, especially in adipose tissue. Bioinformatic methods were used to predict the amino acid sequences, secondary and tertiary structures, and gene locations for ATGL genes and encoded proteins using data from several vertebrate genome projects. ATGL genes usually contained nine coding exons for each of the vertebrate genomes examined, whereas the invertebrate sea squirt (Ciona intestinalis) ATGL gene contained a single exon. Vertebrate ATGL subunits contained 473-504 residues, shared >46% sequence identities, and exhibited sequence alignments and identities for key amino acid residues and predicted motifs: an N-terminal lipid binding region (residues 7-29 for human ATGL); a patatin "motif" (residues 10-179); a putative active site oxyanion "hole" (Cys15, Gly16, and Leu18); and catalytic dyad active site residues (Ser47 and Asp166). Predicted tertiary structures for the ATGL patatin "motif" were similar to those reported for potato patatin, suggesting that this structure is strongly conserved during animal and plant evolution. Human ATGL contained a CpG131 island within the gene promoter; miR-124/506 and miR-108 binding sites within the mRNA 3'-noncoding region; several transcription factor binding sites, including PPARA and PPARG, which are key regulators of genes encoding enzymes of lipid metabolism; and exhibited wide tissue expression at a higher than average level (2.2ש. Phylogenetic analyses of vertebrate PNPLA-like gene families suggest that ATGL is an ancient gene in vertebrate evolution which has been derived from an ancestral ATGL gene (encoding adipose triglyceride lipase) and undergone successive gene duplication events, forming ancestral genes for vertebrate PNPLA1, ATGL, PNPLA3, PNPLA4, and PNPLA5 gene families.