Autophagy genes are required for normal lipid levels in C. elegans

Sanford-Burnham Medical Research Institute
Autophagy (Impact Factor: 11.75). 01/2013; 9(3). DOI: 10.4161/auto.22930
Source: PubMed


Autophagy is a cellular catabolic process in which various cytosolic components are degraded. For example, autophagy can mediate lipolysis of neutral lipid droplets. In contrast, we here report that autophagy is required to facilitate normal levels of neutral lipids in C. elegans. Specifically, by using multiple methods to detect lipid droplets including CARS microscopy, we observed that mutants in the gene bec- 1 (VPS30/ATG6/BECN1), a key regulator of autophagy, failed to store substantial neutral lipids in their intestines during development. Moreover, loss of bec-1 resulted in a decline in lipid levels in daf-2 [insulin/IGF-1 receptor (IIR) ortholog] mutants and in germline-less glp-1/Notch animals, both previously recognized to accumulate neutral lipids and have increased autophagy levels. Similarly, inhibition of additional autophagy genes, including unc-51/ULK1/ATG1 and lgg-1/ATG8/MAP1LC3A/LC3 during development, led to a reduction in lipid content. Importantly, the decrease in fat accumulation observed in animals with reduced autophagy did not appear to be due to a change in food uptake or defecation. Taken together, these observations suggest a broader role for autophagy in lipid remodeling in C. elegans.

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Available from: Louis Rene Lapierre, Oct 06, 2015
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    • "Surprisingly, in laboratory conditions C. elegans can overcome the complete loss of the perilipin-related protein W01A8.1, presumably by activating perilipin-independent lipid degradation. Previous work has shown that an additional lipid degradation pathway, autophagy, was important for lipid metabolism in C. elegans (Lapierre et al., 2013), mammals (Singh et al., 2009) as well as in yeast (Van Zutphen et al., 2014). Similarly in Drosophila, which has two perilipins (plin1 and plin2), the double mutants are viable but have small lipid droplets. "
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    ABSTRACT: Perilipins are lipid droplet surface proteins that contribute to fat metabolism by controlling the access of lipids to lipolytic enzymes. Perilipins have been identified in organisms as diverse as metazoa, fungi, and amoebas but strikingly not in nematodes. Here we identify the protein encoded by the W01A8.1 gene in Caenorhabditis elegans as the closest homologue and likely orthologue of metazoan perilipin. We demonstrate that nematode W01A8.1 is a cytoplasmic protein residing on lipid droplets similarly as human perilipins 1 and 2. Downregulation or elimination of W01A8.1 affects the appearance of lipid droplets resulting in the formation of large lipid droplets localized around the dividing nucleus during the early zygotic divisions. Visualization of lipid containing structures by CARS microscopy in vivo showed that lipid-containing structures become gradually enlarged during oogenesis and relocate during the first zygotic division around the dividing nucleus. In mutant embryos, the lipid containing structures show defective intracellular distribution in subsequent embryonic divisions and become gradually smaller during further development. In contrast to embryos, lipid-containing structures in enterocytes and in epidermal cells of adult animals are smaller in mutants than in wild type animals. Our results demonstrate the existence of a perilipin-related regulation of fat metabolism in nematodes and provide new possibilities for functional studies of lipid metabolism.
    PeerJ 09/2015; DOI:10.7717/peerj.1213 · 2.11 Impact Factor
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    • "observations in mammalian systems, inactivation of autophagy genes in C. elegans results in enhanced staining of gut granules or lysosome related organelles during fasting (Huang et al., 2014). In contrast to this though, it has been reported that inactivation of autophagy genes in C. elegans results in reduction of lipid stores when assessed by other methods (Lapierre et al., 2013b). The precise mechanistic reasons for these opposite outcomes are not yet clear. "
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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.
    Critical Reviews in Biochemistry and Molecular Biology 09/2014; 50(1):1-16. DOI:10.3109/10409238.2014.959890 · 7.71 Impact Factor
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    • "ement of TFEB activity has emerged as a potential therapeutic approach for multiple lysosomal and protein aggregation disorders ( Decressac et al . , 2013 ; Pastore et al . , 2013 ; Spampanato et al . , 2013 ) . Likewise , C . elegans HLH - 30 was implicated in autophagy - mediated longevity exten - sion in long - lived gonad - deficient animals ( Lapierre et al . , 2013b ) . Thus , TFEB has recently emerged as a nutritionally con - trolled stress - response factor . Here we report that , in addition to its known role in nutritional stress , TFEB is also important for host defense against infection . HLH - 30 was activated early during infection , and mutants lack - ing HLH - 30 exhibited a profound host"
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    ABSTRACT: Animal host defense against infection requires the expression of defense genes at the right place and the right time. Understanding such tight control of host defense requires the elucidation of the transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection.
    Immunity 05/2014; 40:1. DOI:10.1016/j.immuni.2014.05.002 · 21.56 Impact Factor
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