Genetic Regulation of Unsaturated Fatty Acid Composition in C. elegans

Institute of Biological Chemistry, Washington State University, پولمن، واشینگتن, Washington, United States
PLoS Genetics (Impact Factor: 7.53). 08/2006; 2(7):e108. DOI: 10.1371/journal.pgen.0020108
Source: PubMed


The ratio of saturated to unsaturated fatty acids has a profound affect on the fluidity and function of cellular membranes. Animals, plants, and microorganisms regulate the synthesis of unsaturated fatty acids during changing environmental conditions, as well as in response to dietary nutrients. In this paper the authors use a combination of genetic and biochemical approaches to address the regulation of unsaturated fatty acid synthesis in the roundworm Caenorhabditis elegans. They identify a new transcription factor, NHR-80, that activates the expression of genes encoding delta-9 fatty acid desaturases, the enzymes responsible for catalyzing the insertion of double bonds into saturated fatty acid chains. These unsaturated fatty acids are critical components of membranes, as well as fat storage molecules. Experiments presented here demonstrate that the worms require adequate synthesis of unsaturated fatty acids for survival and that they maintain intricate regulation of the three delta-9 desaturase genes in response to different nutrients. Abnormalities in lipid metabolism lead to obesity and diabetes in humans; this study contributes to our understanding of the regulation of this metabolic pathway.

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    • "We examined the function of the related C. elegans MAF polymerase III Regulator-1 (MAFR-1) protein and elucidated the functional consequences of altered mafr-1 expression on development, reproduction, and lipid homeostasis. In C. elegans, metabolic homeostasis is maintained by multiple evolutionarily conserved mechanisms (Barros et al., 2012; Brey et al., 2009; Brock et al., 2006, 2007; O'Rourke et al., 2009; Paek et al., 2012; Soukas et al., 2009; Walker et al., 2011; Watts, 2009; Zheng and Greenway, 2012), and C. elegans has become exceptionally useful for high-throughput screening studies of complex cellular processes relevant to human diseases (Anastassopoulou et al., 2011; Squiban et al., 2012; Wä hlby et al., 2012). We have discovered that MAFR-1 negatively regulates intracellular lipid accumulation and influences reproductive capacity. "
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    ABSTRACT: Maf1 is a conserved repressor of RNA polymerase (Pol) III transcription; however, its physiological role in the context of a multicellular organism is not well understood. Here, we show that C. elegans MAFR-1 is functionally orthologous to human Maf1, represses the expression of both RNA Pol III and Pol II transcripts, and mediates organismal fecundity and lipid homeostasis. MAFR-1 impacts lipid transport by modulating intestinal expression of the vitellogenin family of proteins, resulting in cell-nonautonomous defects in the developing reproductive system. MAFR-1 levels inversely correlate with stored intestinal lipids, in part by influencing the expression of the lipogenesis enzymes fasn-1/FASN and pod-2/ACC1. Animals fed a high carbohydrate diet exhibit reduced mafr-1 expression and mutations in the insulin signaling pathway genes daf-18/PTEN and daf-16/FoxO abrogate the lipid storage defects associated with deregulated mafr-1 expression. Our results reveal physiological roles for mafr-1 in regulating organismal lipid homeostasis, which ensure reproductive success. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Preview · Article · Dec 2014 · Cell Reports
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    • "Heterodimerization with other nuclear hormone receptors is a key mechanism through which transcriptional specificity of NHR-49 is mediated. The expression of D9 desaturases fat-5, fat-6 and fat-7 is promoted by NHR-80 (Brock et al., 2006). NHR-49 interacts with NHR-80 and NHR-13 to promote the transcription of these genes and with NHR-66 to repress the transcription of phospholipid and sphingolipid metabolism genes (Pathare et al., 2012). "
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    ABSTRACT: Abstract C. elegans provides a genetically tractable system for deciphering the homeostatic mechanisms that underlie fat regulation in intact organisms. Here, we provide an overview of the recent advances in the C. elegans fat field with particular attention to studies of C. elegans lipid droplets, the complex links between lipases, autophagy, and lifespan, and analyses of key transcriptional regulatory mechanisms that coordinate lipid homeostasis. These studies demonstrate the ancient origins of mammalian and C. elegans fat regulatory pathways and highlight how C. elegans is being used to identify and analyze novel lipid pathways that are then shown to function similarly in mammals. Despite its many advantages, study of fat regulation in C. elegans is currently faced with a number of conceptual and methodological challenges. We critically evaluate some of the assumptions in the field and highlight issues that we believe should be taken into consideration when interpreting lipid content data in C. elegans.
    Full-text · Article · Sep 2014 · Critical Reviews in Biochemistry and Molecular Biology
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    • "Mutations in the daf-2 gene encoding the nematode insulin/IGF receptor cause increased lipid deposition compared to wild type worms [18]. By contrast, lesions in the Δ9 fatty acid desaturases FAT-6 and FAT-7 diminish intestinal fat content [19], [20]. THG imaging confirmed previously reported, dye-based and label-free CARS/SRS observations relevant to fat storage in these mutants (Figure 3a, b). "
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    ABSTRACT: Elucidation of the molecular mechanisms regulating lipid storage and metabolism is essential for mitigating excess adiposity and obesity, which has been associated with increased prevalence of severe pathological conditions such as cardiovascular disorders and type II diabetes, worldwide. However, imaging fatty acid distribution and dynamics in vivo, at the cellular or organismal level is challenging. We developed a label-free method for visualizing lipid depositions in vivo, based on third harmonic generation (THG) microscopy. THG imaging requires a single pulsed-laser light source, alleviating the technical challenges of implementing coherent anti-Stokes Raman scattering spectroscopy (CARS) to detect fat stores in living cells. We demonstrate that THG can be used to efficiently and reliably visualize lipid droplets in Caenorhabditis elegans. Thus, THG microscopy offers a versatile alternative to fluorescence and dye-based approaches for lipid biology research.
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