Linking phospholipid metabolism to membrane and organelle function
Lipids are building blocks for membranes and their regulated production during development often underlies striking morphological changes in a variety of specialized cell types. In addition, lipids act as signals by which organelles and cells communicate with each other and as energy storage molecules. Defects in lipid metabolism or signalling can lead to a large number of disorders such as metabolic syndrome or cancer.
The aim of our laboratory is to understand how cells maintain lipid and membrane homeostasis during growth and development. Our current studies focus on a fundamental step in lipid metabolism, the dephosphorylation of phosphatidic acid (PA) to diacylglycerol (DAG), which is catalysed by a conserved family of lipid phosphatases, lipins. DAG generated by lipins is used for the biosynthesis of (a) membrane phospholipids and (b) triglyceride stored in lipid droplets. Consistent with these essential metabolic functions, lipins are important regulators of both organelle biogenesis and fat storage in many eukaryotic cells.
Using genetic approaches in the model eukaryote Saccharomyces cerevisiae, we have identified the key regulators of the yeast lipin Pah1 that are conserved in mammals, and proposed a model for how these cooperate to recruit Pah1 onto membranes for DAG production. We are currently expanding these studies to both mouse and human fat cells (adipocytes) that express lipin 1, 2 and 3 and investigating their roles both during adipocyte differentiation and lipogenesis.
Unexpectedly, lipins also translocate into the nucleus where they regulate gene expression. We are using a combination of genetics and gene expression profiling approaches to identify the nuclear targets of lipins and uncover the function of these lipid phosphatases in the nucleus.
Sembongi, H., Miranda, M., Han, G.S., Fakas, S., Grimsey, N., Vendrell, J. Carman, G.M. and Siniossoglou, S. Distinct roles of the phosphatidate phosphatases lipin 1 and 2 during adipogenesis and lipid droplet biogenesis in 3T3-L1 cells. J. Biol. Chem. 288, 34502–34513 (2013).
Karanasios, E., Barbosa, A.D., Sembongi, H., Mari, M., Han, G.S., Reggiori, F., Carman, G.M. and Siniossoglou, S. Regulation of lipid droplet and membrane biogenesis by the acidic tail of the phosphatidate phosphatase Pah1p. Mol. Biol. Cell 24, 2124–2133 (2013).
Siniossoglou, S. Phospholipid metabolism and nuclear function: roles of the lipin family of phosphatidic acid phosphatases. Biochim. Biophys. Acta 1831, 575–581 (2013).
Mylonis, I., Sembongi, H., Befani, C., Liakos, P., Siniossoglou, S. and Simos, G. Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J. Cell Sci. 125, 3485–3493 (2012).
Karanasios, E., Han, G.-S., Xu, Z., Carman, G.M. and Siniossoglou, S. A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase. Proc. Natl Acad. Sci. USA 107, 17539–17544 (2010).