Peroxisome proliferator-induced long chain acyl-CoA thioesterases comprisea highly conserved novel multi-gene family involved in lipid metabolism

Long chain acyl-CoA esters are important intermediates in degradation and s ynthesis of fatty acids, as well as having important functions in regulatio n of intermediary metabolism and gene expression. Although the physiologica l functions for most acyl-CoA thioesterases have not yet been elucidated, p revious data suggest that these enzymes may be involved in lipid metabolism by modulation of cellular concentrations of acyl-CoAs and fatty acids. In line with this, we have cloned four highly homologous acyl-CoA thioesterase genes from mouse, showing multiple compartmental localizations. The nomenc lature for these genes has tentatively been assigned as CTE-I (cytosolic), MTE-I (mitochondrial), and PTE-Ia and Ib (peroxisomal), based on the identi fication of putative targeting signals. Although the various isoenzymes sho w between 67% and 94% identity at amino acid level, each individual enzyme shows a specific tissue expression. Our data suggest that all four genes ar e located within a very narrow cluster on chromosome 12 in mouse, similar t o a sequence cluster on human chromosome 14, which identified four genes ho mologous to the mouse thioesterase genes. Four related genes were also iden tified in Caenorhabditis elegans, all containing putative PTS1 targeting si gnals, suggesting that the ancestral type I thioesterase gene(s) is/are of peroxisomal origin. All four thioesterases are differentially expressed in tissues examined, but all are inducible at mRNA level by treatment with the peroxisome proliferator clofibrate, or during the physiological condition of fasting, both of which conditions cause a perturbation in overall lipid homeostasis. These results strongly support the existence of a novel multi- gene family cluster of mouse acyl-CoA thioesterases, each with a distinct f unction in lipid metabolism.