Uncovering novel regulators of lipid metabolism

Membrane and storage lipids respond to cellular needs by undergoing constant cycles of synthesis, recycling and degradation. Maintaining a well-balanced cellular fatty acid (FA) composition is crucial for membrane structure and function, yet, the molecular mechanisms underlying the FA fluxes into either storage or membrane lipids are literally unknown. An imbalance in FA synthesis or detoxification of excess FA into triyglycerides contributes to lipotoxicity and may ultimately result in cell death. To date, a number of acyltransferases have been characterized, catalyzing the incorporation of FA into various lipids. Recently, we discovered that a yeast mutant devoid of the four acyltransferases Dga1p, Lro1p, Are1p, and Are2p and thus lacking triglycerides and steryl esters altogether, is sensitive to an excess of unsaturated FA, but not of saturated FA: Unsaturated FA are primarily diverted towards phospholipids and ultimately result in cell death due to massive membrane proliferations, whereas saturated FA do not significantly change PL patterns (Petschnigg et al., 2009). Based on our observations, we hypothesize that biosynthesis and subcellular distribution of lipids are tightly coordinated, and that these processes are controlled by direct molecular interactions of the involved enzymes and potential mediators. The aim of this proposal is thus to dissect the protein network governing the flux of fatty acids and the central role of acyltransferases in this "metabolic channeling" process. Specifically, I propose to perform protein-protein interaction studies with both yeast and mammalian acyltransferases and perform a combined biochemical and genomics approach to identify as yet unknown proteins harboring diverse functions in controlling fatty acid fluxes. Since these processes are considerably conserved in yeast, we expect that the outcome of these studies will also be relevant for understanding these processes in mammalian cells.