Lipins: Linking phospholipid biosynthesis to organelle biogenesis

Lead Research Organisation: University of Cambridge
Department Name: Cambridge Institute for Medical Research

Abstract

Cells use lipids as building blocks for the formation of membranes. Membranes separate cells from their environment and are also essential for the organization of the intracellular space into several compartments, or organelles, each with its own specific function. Lipids determine the physical properties of membranes, such as their ability to change shape and their permeability. Moreover, lipids can produce chemical messages and thus local changes in lipid composition affect the way organelles communicate with each other. The main aim of this project is to understand how a family of enzymes, conserved from yeasts to humans, regulates lipid production and how this in turn impacts on membrane biogenesis and organelle structure/function. Some of these enzymes control also production of triglycerides, the major energy store in fat cells and there is evidence that their mutation disrupts fat metabolism. By studying how these enzymes function, we hope to learn more about conditions like obesity and lipodystrophy.

Technical Summary

Biological membranes consist of a complex mixture of lipids that are key determinants of their physical properties. Phospholipid production and distribution between different membranes are important factors determining the shape and function of many organelles. Recent studies from our lab have identified a network of evolutionarily conserved genes in yeast that couple phospholipid biosynthesis with nuclear membrane growth. The main effector of this pathway is Pah1p/Smp2p, a phosphatidic acid phosphatase that controls a key step in phospholipid synthesis. Mammals express three Pah1p homologues, Lipin 1, 2 and 3. Unpublished work from our lab shows that Lipins are also important for nuclear structure. We plan now to investigate how Lipins control phospholipid synthesis in mammalian cells, how regulation of their membrane recruitment and enzyme activity controls nuclear structure and whether they have additional functions in other organelles. In addition, since the Lipin-Pah1 pathway is conserved from unicellular eukaryotes to mammals, we will use yeast genetics to explore the mechanism by which phospholipids control nuclear structure, characterize novel Pah1p-interacting proteins and then focus on their mammalian orthologues.

Lipins also catalyze the penultimate step in the pathway to synthesize triacylglycerol (TAG), the major energy store in adipocytes. The importance of this step in fat metabolism is highlighted by the fact that, in mice, mutations in Lipin 1 cause lipodystrophy whereas overexpression causes diet-induced obesity. The proposed study will provide key insights into the molecular and cellular pathways that regulate the activity of Lipins and this, in turn, will lead to a better understanding of phospholipid and TAG metabolism. These insights could also contribute to the development of new therapeutic strategies to control body fat, either by targeting Lipins themselves or regulators of their activity.

Publications

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Barbosa AD (2015) Lipid partitioning at the nuclear envelope controls membrane biogenesis. in Molecular biology of the cell

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Barbosa AD (2017) Function of lipid droplet-organelle interactions in lipid homeostasis. in Biochimica et biophysica acta. Molecular cell research

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Barbosa AD (2016) Spatial distribution of lipid droplets during starvation: Implications for lipophagy. in Communicative & integrative biology

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Barbosa AD (2015) Lipid droplet-organelle interactions: emerging roles in lipid metabolism. in Current opinion in cell biology

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Grimsey N (2008) Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2. in The Journal of biological chemistry

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Han GS (2008) Characterization of the yeast DGK1-encoded CTP-dependent diacylglycerol kinase. in The Journal of biological chemistry

 
Description Seed Award
Amount £100,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 08/2017
 
Title antibodies against mammalian lipin 1, 2 and 3 
Description Affinity purified antibodies against three key enzymes of lipid and fat metabolism (Lipin 1, 2 and 3) 
Type Of Material Antibody 
Year Produced 2008 
Provided To Others? Yes  
Impact in progress 
 
Description Conserved mechanisms of lipid droplet biogenesis 
Organisation Medical Research Council (MRC)
Department MRC Centre for Obesity and Related Metabolic Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution Advising and providing reagents for the study of lipid droplets using a unicellular yeast model.
Collaborator Contribution Advising and providing reagents for the study of lipid droplets using a mouse model
Impact Rowe et al, JBC 2016 (26742848)
Start Year 2012
 
Description Enzymology of lipins in yeast cells 
Organisation Rutgers University
Department Department of Food Science
Country United States 
Sector Academic/University 
PI Contribution In vivo cell biological analysis of enzymes using both yeast and mammalian tissue culture as model systems
Collaborator Contribution Collaborator is expert on lipid enzymology and provides useful kinetic data on the enzymes we are studying
Impact Papers: 16968695 17910939 17971454 18458075 18458076
Start Year 2006
 
Description Function of lipins in human adipocyte differentiation 
Organisation Rovira i Virgili University
Country Spain 
Sector Academic/University 
PI Contribution Applying cell biological methods to analyze the function of lipins in human adipocytes in tissue culture
Collaborator Contribution Establishing methods to analyze the function of lipins in human adipocytes obtained from fat biopsies Providing human adipogenic cell lines to study the function of lipins in tissue culture
Impact One paper under revision in Diabetologia (Temprano et al, 2016)
Start Year 2011
 
Description High content GFP screening of yeast mutants 
Organisation Weizmann Institute of Science
Country Israel 
Sector Academic/University 
PI Contribution We are studying fat storage using budding yeast as a model system. We have identified a novel pathway involved in fat storage.
Collaborator Contribution The Schuldiner group in the Weizmann Institute for Science has established technologies that allow the rapid and unbiased identification of protein localization factors and functional interactions at a genome-wide scale. They will use their know-how to screen for factors controlling fat storage in yeast cells.
Impact no papers published yet from this collaboration
Start Year 2016
 
Description Role of lipins in hypoxia 
Organisation University of Thessaly
Department Laboratory of Biochemistry
Country Greece 
Sector Academic/University 
PI Contribution Assays to visualize intracellular distribution of lipins in tissue culture cells
Collaborator Contribution Assays to quantify the effects of lipins in hypoxia
Impact Two papers 22467849 25744540
Start Year 2011
 
Description Ultrastructural analysis of lipid droplet biogenesis 
Organisation University Medical Center Gronigen
Department Department of Cell Biology
Country Netherlands 
Sector Academic/University 
PI Contribution Generation of cell lines and yeast strains with altered lipid droplet content
Collaborator Contribution Morphometric analysis and quantification of lipid droplets in yeast and mammalian model systems by electron microscopy
Impact Two papers: 23657815, 26269581
Start Year 2013