The first part of our work is concerned with signal transduction by lipid messengers, which are produced by agonists that activate receptors and phospholipases. For example, the receptor-mediated productions of phosphatidate (PA), lysophosphatidate (LPA), diacylglycerol (DAG), ceramide 1-phosphate (C1P) and sphingosine 1-phosphate (S1P) in cells represent powerful mitogenic signals, whereas ceramides can produce death (apoptosis) in some cells. Our work focuses on a family of lipid phosphate phosphatases (LPPs) that terminate signal transduction by PA, LPA, C1P and S1P through dephosphorylating these second messengers. At the same time the LPPs generate other signals by producing DAG, ceramide or sphingosine. Our work involves over-expressing or decreasing the activities of the different LPP isoforms, creating mutants and studying their covalent modifications and turnovers. These techniques also enable us to investigate the role of the LPPs in regulating cell signaling by LPA and S1P that are produced outside the cell and act on families of G-protein coupled receptors. These receptors stimulate cell division, wound repair, the development of new blood vessels (angiogenesis), the growth of tumors and their spread to other parts of the body (metastasis). We are determining how the LPPs controls cell migration, division and cell death. This work has application in understanding processes that control wound healing, tumor growth, metastasis, angiogenesis and the efficacy of chemotherapy.

The second part of our work is concerned with another phosphatase, phosphatidate phosphatase-1 (PAP1). The Group produced much of the pioneering work on PAP1, which showed that PAP1 is an essential enzyme that regulates the synthesis of triacylglycerols (TAG), phosphatidylcholine and phosphatidylethanolamine. The structure of PAP1 was unknown until 2006 when PAP1 was shown to belong to a family of lipin proteins. The lipins not only regulate lipid synthesis, but they also act as transcriptional co-activators. Lipin -1&alpha -1&beta, (splice variants) are the major lipins in adipose tissue and they are required for the activation of peroxisome proliferator activated receptor-γ (PPAR&gamma) and the differentiation of pre-adipocytes into mature adipocytes. The liver expresses lipin-1&alpha, -1&beta, lipin-2 and lipin-3. We showed that synthesis of lipin-1&alpha and -1&beta, and not lipin-2 and -3 is induced by glucocorticoids (cortisol) together with glucagon and that insulin acts antagonistically. This increases the capacity of the liver to synthesize TAG in starvation, insulin resistance, obesity and diabetes. In addition, lipin-1 interacts with peroxisome proliferator activated receptor-coactivator-1&alpha (PGC-1&alpha and PPAR&alpha and this stimulates the production of enzymes involved in fatty acid oxidation and the secretion of TAG in very low density lipoproteins. The activity of lipin-1 is also regulated by its phosphorylation and ability to translocate from the cytosol to the endoplasmic reticulum and nucleus. We are investigating the role of different phosphorylation sites in regulating lipin activity. Our work is directed to understanding how the lipins control the metabolism of the liver, heart and adipose tissue and thus the predisposition to premature cardiovascular disease in insulin resistance, obesity and diabetes.

For more information on Dr Brindley's research, also see his listing in the Community of Science database.