Involvement of 4E-BP1 in the protection induced by HDLs on pancreatic beta-cells.
High-density lipoproteins (HDLs) protect pancreatic beta-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 beta-cells are poorly characterized. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in beta-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-1beta, and this was blunted by HDLs. Whereas an ectopic increase of 4E-BP1 expression induced beta-cell death, silencing 4E-BP1 increase with short hairpin RNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect beta-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 beta-cells through modulation of 4E-BP1 depending on the type of stress stimuli.
Pétremand
Jannick
J
Department of Physiology, Lausanne University, 1005 Lausanne, Switzerland.
Bulat
Natasa
N
Butty
Anne-Christine
AC
Poussin
Carine
C
Rütti
Sabine
S
Au
Karin
K
Ghosh
Sujoy
S
Mooser
Vincent
V
Thorens
Bernard
B
Yang
Jiang-Yan
JY
Widmann
Christian
C
Waeber
Gérard
G
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D019610:Cytoprotection / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D044967:Serum; D013312:Stress, Physiological / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D015415:Biomarkers; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D053583:Interleukin-1beta; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D010750:Phosphoproteins; D002784:Cholesterol