Abstract
Monomethyl branched-chain fatty acids (mmBCFAs) are commonly found in many organisms from bacteria to mammals. In humans, they have been detected in skin, brain, blood, and cancer cells. Despite a broad distribution, mmBCFAs remain exotic in eukaryotes, where their origin and physiological roles are not understood. Here we report our study of the function and regulation of mmBCFAs in Caenorhabditis elegans, combining genetics, gas chromatography, and DNA microarray analysis. We show that C. elegans synthesizes mmBCFAs de novo and utilizes the long-chain fatty acid elongation enzymes ELO-5 and ELO-6 to produce two mmBCFAs, C15ISO and C17ISO. These mmBCFAs are essential for C. elegans growth and development, as suppression of their biosynthesis results in a growth arrest at the first larval stage. The arrest is reversible and can be overcome by feeding the arrested animals with mmBCFA supplements. We show not only that the levels of C15ISO and C17ISO affect the expression of several genes, but also that the activities of some of these genes affect biosynthesis of mmBCFAs, suggesting a potential feedback regulation. One of the genes, lpd-1, encodes a homolog of a mammalian sterol regulatory element-binding protein (SREBP 1c). We present results suggesting that elo-5 and elo-6 may be transcriptional targets of LPD-1. This study exposes unexpected and crucial physiological functions of C15ISO and C17ISO in C. elegans and suggests a potentially important role for mmBCFAs in other eukaryotes.
Highlights
Fatty acids (FAs) belong to a physiologically important class of molecules involved in energy storage, membrane structure, and various signaling pathways
Molecular, and biochemical analyses, we show that the worm is able to synthesize monomethyl branched-chain fatty acid (mmBCFA) de novo but is absolutely dependent on these FA species for its growth and development
The RNAi of elo-6 significantly reduced the amount of only C17ISO, while the RNAi of elo-5 dramatically reduced quantities of both C15ISO and C17ISO (Figure 3). These results indicate that ELO-5 might be involved in the biosynthesis of C15ISO and possibly C17ISO, whereas ELO-6 may function in elongating C15ISO to C17ISO (Figure 3C and 3D)
Summary
Fatty acids (FAs) belong to a physiologically important class of molecules involved in energy storage, membrane structure, and various signaling pathways. These data indicate that, in addition to regulating the first steps of global FA biosynthesis through the activation of the ACC and FAS transcription, the worm SREBP homolog regulates mmBCFA elongation as well as desaturation of straight-chain FAs. As reported previously, disruption of lpd-1 through a mutation or RNAi injection caused early larval arrest (McKay et al 2003). In the elo5(RNAi) animals fed with C15ISO or C15anteISO containing bacterial supplement (S. maltophilia), the FA composition was significantly altered (see Figure 6E) It appears that mmBCFAs become principal components in a range of 16–18-carbon FAs. It appears that mmBCFAs become principal components in a range of 16–18-carbon FAs This suggests that large quantities of mmBCFAs are not toxic. It is important to screen for such interactions to better understand FA homeostasis in C. elegans
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