Person:

Stanya, Kristopher J

Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling metabolic dysfunction associated with chronic inflammation remains unexplored. We demonstrate here that administration of Lacto-N-fucopentaose III (LNFPIII), a LewisX containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased Il-10 production by LNFPIII activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment up-regulates nuclear receptor Fxr-α (or Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-Ap1 pathway appears to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide novel therapeutic approaches to treat metabolic diseases.

Corepressors are large proteins that facilitate transcriptional repression through recruitment of histone-modifying enzymes. Two major corepressors, SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor corepressor), have been shown to mediate repression associated with nuclear receptors and a myriad of other transcription factors. This review will focus on recent studies on these proteins, including newly discovered physiological roles of the corepressors, their modes of regulation, their roles in antiestrogen-resistant breast cancer and their functions during the cell cycle.