Our interests in FA biosynthesis and homeostasis were induced by our previous genetic studies on several genes involved in human macular dystrophy (1-4). In collaboration with others, we have mapped and cloned one gene with a dominant form of macular degeneration (3-4). This gene encodes a long chain FA elongation enzyme, ELOVL4. Realizing the importance of FA to human health, we have initiated studies of FA metabolism using C. elegans. The animal model allows effective combination of genetics, biochemical and molecular analyses to address fundamental problems regarding physiological roles of FA and FA homeostasis. We have recently reported the analysis of genes involved in long chain FA synthesis (5). We have shown that the predicted C. elegans ELO-2 is a functional enzyme responsible for the elongation of palmitate and that it is involved in polyunsaturated FA biosynthesis. Disruption of the ELO-2 function causes imbalance in the FA composition resulting in multiple defects such as slow growth, small body size, reproductive defects, and changes in rhythmic behavior. Continuing the study we addressed the functions of SREBP (sterol regulatory element binding protein and several other FA elogation enzymes, using RNAi, gas chromatography, and microarray techniques. We have determined that in addition to elo-1
, two other predicted elo genes are essential for maintaining a proper FA composition. We learned that all four genes, as well as several FA desaturase genes, are transcriptionally regulated by SREBP, suggesting the role of SREBP in FA biosynthesis in C. elegans. In the course of this study, we have discovered the crucial physiological roles performed by branched chain saturated FAs. The later result is very significant because it is the first indication of biological activity of this group of FAs in metazoan. The roles of branched FAs in specific biological processes as well as regulation of FA balance are being further investigated. (1) Kniazeva, et al., 1999a. Am J Hum Genet 64: 1394-9.; (2) Kniazeva, et al., 1999b. Ophthalmic Genet 20: 71-81; (3) Kniazeva, et al., 2000.Am J Ophthalmol 130: 197-202. (4) Zhang, K., et al. 2001. Nat Genet 27: 89-93; (5) Kniazeva, M et al., 2003 Genetics 163: 159-69.