Lipins: Linking phospholipid biosynthesis to organelle biogenesis

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.

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 Unpublished work from our lab shows that Lipins are also important for nuclear structure.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.