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Involvement of 4E-BP1 in the Protection Induced by HDLs on Pancreatic β-Cells

Department of Physiology (J.P., N.B., C.P., B.T., J.-Y.Y., C.W.), Department of Cell Biology and Morphology (J.P., N.B., A.-C.B., J.-Y.Y., C.W.), Lausanne University, 1005 Lausanne, Switzerland; Center for Integrative Genomics (C.P., B.T.), Lausanne University, 1015 Lausanne, Switzerland; Department of Internal Medicine (A.-C.B., G.W.), University Hospital Center, 1011 Lausanne, Switzerland; GlaxoSmithKline R&D Drug Discovery (K.A., S.G., V.M.), Research Triangle Park, North Carolina 27709, and King of Prussia, Pennsylvania 19406; and Division of Endocrinology and Diabetes (S.R.), 8091 University Hospital Zürich, Zürich, Switzerland

Address all correspondence and requests for reprints to: Christian Widmann, Department of Physiology, Rue du Bugnon 7/9, 1005 Lausanne, Switzerland. E-mail: Christian.Widmann{at}unil.ch.

High-density lipoproteins (HDLs) protect pancreatic β-cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. However, the mechanisms by which HDLs protect β-cells are poorly characterized. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in β-cells subjected to apoptotic stimuli. The transcript encoding 4E-binding protein (4E-BP)1 was up-regulated by serum starvation, and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its non- or hypophosphorylated state but it loses this ability when hyperphosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL-1β, and this was blunted by HDLs. Whereas an ectopic increase of 4E-BP1 expression induced β-cell death, silencing 4E-BP1 increase with short hairpin RNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect β-cells by blocking 4E-BP1 protein expression, but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by endoplasmic reticulum stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect β-cells through modulation of 4E-BP1 depending on the type of stress stimuli.