Cholesterol Regulates Glucose-stimulated Insulin Secretion through Phosphatidylinositol 4,5-Bisphosphate*

AUTOR(ES)

Hao, Mingming

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

Membrane cholesterol modulates the ability of glucose to stimulate insulin secretion from pancreatic β-cells. The molecular mechanism by which this occurs is not understood. Here, we show that in cultured β-cells, cholesterol acts through phosphatidylinositol 4,5-bisphosphate (PIP2) to regulate actin dynamics, plasma membrane potential, and glucose-stimulated insulin secretion. Cholesterol-overloaded β-cells exhibited decreased PIP2 hydrolysis, with diminished glucose-induced actin reorganization, membrane depolarization, and insulin secretion. The converse findings were observed in cholesterol-depleted cells. These results support a model in which cholesterol depletion is coupled through PIP2 to enhance both plasma membrane Ca2+ influx from the extracellular space, as well as inositol 1,4,5-triphosphate-stimulated Ca2+ efflux from intracellular stores. The inability to increase cytosolic Ca2+ may be the main underlying factor to account for impaired glucose-stimulated insulin secretion in cholesterol-overloaded β-cells.

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