Lipids: Metabolism, Nutrition & Health

Biography

Biography: Sasanka Ramanadham

Abstract

  Type 1 diabetes   (T1D) is a consequence of pancreatic islet b-cell destr uction, due to  apoptosis . Our lab is in vestigating underlying mechanisms that contribute to b-cell loss and we identified a prominent role for the group VIA Ca²⁺-independent   phosphoplipase   A₂b (iPLA₂b) in this process. The cytosolic iPLA₂b catalyzes   hydrolysis   of the sn-2 sbstituent from membrane   phopsholipids  . The islet b-cell membranes are enriched in arachidonate-containing phospholipids and activation of iPLA₂b in the b-cells leads to accumulations in   arachidonic acid   and its various oxidized metabolites (i.e. eicosanoids). The eicosanoids manifest different activities, some of which are proinflammatory and apoptotic and some are ant-inflammatory and anti-apoptotic. Inhibition, knockdown, or knockout of iPLA₂b significantly reduces   b-cell apopotosis   due to  ER stress  or proinflammatory cytokines. Further, d uring the development of autoimmune T1D, expression and activity of iPLA₂b increases and this is associated with generation of proinflammatory and  apoptotic lipid  signals. Consistent with this, we find that with selective inhibition of iPLA₂b in the spontaneously diabetes-prone non-obese diabetic (NOD) mouse, there is a significant reduction in islet infiltration by  leukocyte s, preservation of b-cell mass, and a dramatic amelioration of T1D. We further find that iPLA ₂b inhibition markedly reduces immune responses. These observations provide strong evidence for contribution of iPLA₂b-derived lipids to T1D development. Our on-going investigations reveal that activation of iPLA₂b triggers molecular mechanisms that favor generation of pro -apoptotic/pro-inflammatory signals and these work in concert to promote T1D development. Our work was supported by the American Diabetes Association, NIH/NIDDK, and the Iacocca Family Foundation.