Linking phospholipid metabolism to membrane and organelle function
General audience summary:
Cells use lipids as building blocks to form their membranes and as storage molecules to preserve energy for later use. Membranes separate cells from the environment, and continuous membrane synthesis is required for cell growth and proliferation while the ability to store energy in the form of triacylglycerol (or fat) in lipid droplets is essential for survival during nutritional or environmental stress. Our aim is to understand how different lipids are made and the mechanisms by which cells partition them between membranes for growth or lipid droplets for energy storage. This understanding is vital as disruption of the balanced use and processing of lipids in cells can result in several pathologies and is at the heart of the current obesity epidemic.
Strategic CIMR theme: Organelle Biology
Funding: BBSRC
Research group members: Shiyu Guo
Research
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.
Control of lipid partitioning by the conserved yeast lipin Pah1. Loss of Pah1 results in de-repressed nuclear/ER membrane proliferation (arrows, left panel). Conversely, constitutive activation of Pah1 results in lipid droplet accumulation (arrows, right panel).
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.
The mouse lipin 1 is required for lipid droplet biogenesis in differentiating mouse adipocytes. 3T3-L1 cells treated with control siRNA (left panel) or lipin 1 siRNA (right panel). Droplets are labelled in red.
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.
Publications
Barbosa AD, Lim K, Mari M, Edgar JR, Gal L, Sterk P, Jenkins BJ, Koulman A, Savage DB, Schuldiner M, Reggiori F, Wigge PA, Siniossoglou S. Compartmentalized Synthesis of Triacylglycerol at the Inner Nuclear Membrane Regulates Nuclear Organization. Dev Cell. 50, 755-766 (2019)
Haider A, Wei YC, Lim K, Barbosa AD, Liu CH, Weber U, Mlodzik M, Oras K, Collier S, Hussain MM, Dong L, Patel S, Alvarez-Guaita A, Saudek V, Jenkins BJ, Koulman A, Dymond MK, Hardie RC, Siniossoglou S*, Savage DB*. PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress. Dev. Cell pii: S1534-5807(18)30287-9 (2018) *co-senior authors
Barbosa AD, Siniossoglou S. Function of lipid droplet-organelle interactions in lipid homeostasis. Biochim. Biophys. Acta. 1864(9):1459-1468 (2017).
Temprano A, Sembongi H, Han GS, Sebastián D, Capellades J, Moreno C, Guardiola J, Wabitsch M, Richart C, Yanes O, Zorzano A, Carman GM, Siniossoglou S*, Miranda M*. Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes. Diabetologia. 59(9):1985-94. (2016) * co-senior authors
Barbosa AD, Savage DB, Siniossoglou S. Lipid droplet-organelle interactions: emerging roles in lipid metabolism. Curr. Opin Cell Biol. 35:91-7 (2015).
Barbosa AD, Sembongi H, Su WM, Abreu S, Reggiori F, Carman GM, Siniossoglou S. Lipid partitioning at the nuclear envelope controls membrane biogenesis. Mol. Biol. Cell 26(20):3641-57 (2015).
Karanasios E, Barbosa AD, Sembongi H, Mari M, Han GS, Reggiori F, Carman GM, Siniossoglou S. Regulation of lipid droplet and membrane biogenesis by the acidic tail of the phosphatidate phosphatase Pah1p. Mol. Biol. Cell 24(13):2124-33 (2013).
Karanasios E, Han GS, Xu Z, Carman GM, Siniossoglou S. A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase. Proc. Natl Acad. Sci. USA 107(41):17539-44 (2010).
