Abstract
AMP-activated kinase (AMPK) is a key regulator of many cellular mechanisms required for adjustment to various stresses induced by the changing environment. In C. elegans dauer larvae AMPK-null mutants expire prematurely due to hyperactive Adipose Triglyceride Lipase (ATGL-1) followed by rapid depletion of triglyceride stores. We found that the compromise of one of the three C. elegans orthologues of human cgi-58 significantly improves the survival of AMPK-deficient dauers. We also provide evidence that C. elegans CGI-58 acts as a co-activator of ATGL-1, while it also functions cooperatively to maintain regular lipid droplet structure. Surprisingly, we show that it also acts independently of ATGL-1 to restrict lipid droplet coalescence by altering the surface abundance and composition of long chain (C20) polyunsaturated fatty acids (PUFAs). Our data reveal a novel structural role of CGI-58 in maintaining lipid droplet homeostasis through its effects on droplet composition, morphology and lipid hydrolysis; a conserved function that may account for some of the ATGL-1-independent features unique to Chanarin-Dorfman Syndrome.
Highlights
Most organisms possess a remarkable capacity to sense environmental variation and to modify their physiology to adapt to such changes
Chanarin-Dorfman Syndrome (CDS) is caused by mutation of the cgi-58 gene, which is essential for lipid breakdown, but may have additional cellular functions
To explore how adipose triglyceride lipase (ATGL)-1 may be regulated during the dauer stage, we characterized the function of the C. elegans orthologue of mammalian CGI-58, which we identified in a genome-wide survey for genes that phenocopied atgl-1(RNAi) by enhancing dauer survival of animals with mutations in both isoforms of their AMPK α subunit (aak-1 and aak-2, which will be presented as aak(0) throughout the study) [17]
Summary
Most organisms possess a remarkable capacity to sense environmental variation and to modify their physiology to adapt to such changes. In C. elegans, parallel cross-talk among several genetic pathways determines an “all or none” dauer entry response. This developmental decision is dictated by neuronal sensing of environmental indicators followed by signal transduction in neuroendocrine cells to eventually converge on a nuclear hormone receptor-mediated transcriptional cascade [6]. One of the common targets of these three genetic pathways is the AMP-activated protein kinase (AMPK) [7]. Upon activation by its upstream activating protein kinase LKB1/PAR-4, AMPK will in turn phosphorylate downstream targets to promote catabolic processes while simultaneously blocking anabolic processes to restore energy homeostasis [8,9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
