Downregulation of Cellular Energy Sensor during Disease condition results in Alteration of Lipid Homeostasis in Immune Cells

Abstract

AMP‐activated protein kinase (AMPK), an energy sensing metabolic switch of mammalian cells, was observed to be down regulated during T cells mediated autoimmune disease. A catalytic subunit of AMPK, alpha1, was predominantly expressed in T‐ and antigen presenting cells. During EAE disease, activity of AMPK was significantly downregulated in thymocytes, spleen cells and brain. Decreased AMPK activity results increased lipid biosynthesis and their content in total T cells, adherent and non‐adherent spleen cells at disease state. Increased lipids biosynthesis leads to the higher proliferative state of these cells was evident from active form of Akt, p42/44 and reduced levels of p21 and p27. AMPK activators restored lipid alteration in total spleen cells by reversing the AMPK activity and inhibited production of pro‐inflammatory cytokines under in vitro stimulation. All together, our results demonstrated that downregulation of AMPK‐mediated altered lipid metabolism in immune cells, resulted an inflammatory environment may be one of the critical aspects of pathogenesis during EAE or Multiple Sclerosis and identified AMPK as a novel therapeutic target for autoimmune diseases.Grants support: Mainly by RG 3810‐A‐1 and PP1283 from the MS Society (SG) and in part by (NS‐22576, NS‐34741, NS‐37766 and NS‐40810) from NIH (IS).