Fellowship for Hongmei Ren: Regulation of Triglyceride Synthesis by Membrane Targetting of Lipin/Type 1 Phosphatidic acid Phosphatase

  • Morris, Andrew (PI)
  • Ren, Hongmei (CoI)

Grants and Contracts Details


Phosphorylated derivatives of glycerophospholipids, sphingolipids and isoprenoids are critical intermediates in cellular metabolism and play important roles as messenger molecules in intra and extra- cellular signaling. A long term objective of research in our laboratory is to identify and characterize enzymes and pathways involved in the synthesis and degradation of these lipid phosphate esters and to use this information to gain insights into fundamental mechanisms of human disease. The simple lipid phosphate molecule phosphatidic acid (PA) is a critical intermediate in the de novo synthesis of triglycerides and certain phospholipids. The penultimate step in this pathway involves dephosphorylation of PA to form diacylglycerol (DG) which is then acylated to form triglycerides (TG). Aberrant or excessive accumulation of TGs is central to the development of diet-induced obesity and therefore constitutes a fundamental biochemical basis for the initiation and progression of atherothrombotic, cardiovascular and metabolic disease. The TG synthesis pathway is a prospective target for pharmacological intervention in obesity so a complete knowledge of the enzymes and pathways responsible is necessary for the design and characterization of experimental therapeutics that target this process. This information is also vital for definition of the molecular basis of disorders of lipid metabolism. The goal of this proposal is to address deficiencies in our understanding of the enzymology and regulation of triglyceride synthesis by defining the role of PA phosphatases in this pathway. Specifically, we propose to determine mechanisms controlling the subcellular localization of lipins which are newly identified PA phosphatases responsible for the generation of the DG precursor for TG and phospholipid synthesis. Lipin 1 also functions in the nucleus as a transcriptional activator of PPAR-alpha responsive genes. Lipins are soluble proteins that lack previously identified membrane association motifs yet they act on a membrane- associated substrate. We have identified a conserved motif rich in basic and hydrophobic amino acids in mammalian and yeast lipins that we propose has a dual function as both a membrane anchor and nuclear localization sequence. We will test the hypothesis that membrane targeting mediated by this "polybasic motif" is a critical regulator of the subcellular localization and function of these enzymes in phospholipid and TG synthesis and metabol
Effective start/end date7/1/086/30/10


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