Background and aims: Low level of HDL cholesterol is one of the lipid phenotype
observed in diabetic patients. HDLs exert numerous protective effects
on endothelial cells such as prevention of LDL oxidation, endothelial
dysfunction and apoptosis. In the case of pancreatic beta cells, HDLs have
been shown to protect against apoptosis elicited by various stress stimulus
such as serum starvation, cytokines, or oxidized LDL. However, the molecular
mechanisms of HDL-induced beta cells protection are not entirely identified
and represent a promising way to discover new potential target for the
treatment of diabetes.
Materials and methods: Affymetrix gene chip technology was used in stress
or normal conditions to identify the target genes by which HDL exert their
anti-apoptotic activities in insulin-secreting cells.
Results: One interesting target identified was the translational repressor 4Ebinding
protein (4E-BP1). This small protein regulates protein synthesis by
sequestering eIF4E which is necessary for initiation of translation. 4E-BP1
expression is induced by starvation or hypoxia and has been demonstrated
to induce apoptosis. In this study, stresses such as serum starvation or IL-1
beta treatment induced 4E-BP1 expression in insulin-secreting beta cell lines
and in human islets. The induction of 4E-BP1 expression was significantly
reduced by HDL, and this effect was correlated with prevention of apoptosis.
Moreover, overexpression or lentiviral infection with 4E-BP1 constructs induced
apoptosis, mimicking the starvation effect. Finally, the use of 4E-BP1
shRNA reduced the induction of 4E-BP1 expression by the stress and the
stress-induced apoptotic response was also reduced showing that there is a
direct link between stress conditions, increased 4E-BP1 levels and apoptosis
in beta cells.
Conclusion: These data indicate that HDL block stress-induced expression
of 4E-BP1 and prevent beta cell apoptosis, showing that 4E-BP1 is a possible
target to prevent development of diabetes.