Loss of function mutation in the S adenosylmethionine synthetase 1 gene (sams 1) increases lipogenesis, enlarges lipid droplets and reduces lipolysis efficiency in Caenorhabditis elegans

Cytosolic lipid droplets (LDs) are evolutionary conserved and versatile organelles important for storage and utilization of lipids in almost all cell types. In order to gain insights into the functional connection between LD size and lipid homeostasis we isolated, identified and finally characterized an Sadenosylmethionine synthetase (SAMS1) deficient Caenorhabditis elegans (C. elegans) mutant showing enlarged LDs throughout the life cycle. SAMS1 belongs to a family of evolutionary conserved enzymes, which catalyze the only known route of Sadenosylmethionine (SAM) synthesis. SAMdependent methylation is of quantitative importance for the synthesis of phosphatidylcholine (PC), a major phospholipid of membranes. Syntheses of PC and triacylglycerol (TAG) are intimately coupled to each other due to common intermediates, shared biosynthetic routes and mutual regulatory mechanisms. The present study shows that SAMS1 is necessary for homeostasis of PC and TAG synthesis and that SAMS1 deficiency results in excessive TAG storage in C. elegans. Thin layer chromatography based analysis of lipid extracts revealed that SAMS-1 deficiency reduces PC level but increases TAG proportions. Microarraybased expression profiling identified upregulation of several lipogenic genes due to SAMS1 deficiency, which is supposed to contribute to increased TAG proportions. Vital fat staining via BODIPY™ 493/503 revealed that increased TAG level are stored in fewer but larger LDs in sams1 mutants. A reduced surface area of few large-sized LDs is supposed to represent a mechanism to economize PC. Moreover, sams1 mutants displayed a reduced body size and an impaired reproductive capability. In summary, our data reveal a mechanism of how SAMS1 deficiency mediates increased fat storage through impaired PC synthesis, LD expansion, increased lipogenesis and reduced lipolysis efficiency.



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