Cholesterol Sulfate Exerts Protective Effect on Pancreatic β-Cells by Regulating β-Cell Mass and Insulin Secretion.

Cholesterol sulfate (CS) is the most abundant known sterol sulfate in human plasma, and it plays a significant role in the control of metabolism and inflammatory response, which contribute to the pathogenesis of insulin resistance, β-cell dysfunction and the resultant development of diabetes. However, the role of CS in β-cells and its effect on the development of diabetes remain unknown. Here, we determined the physiological function of CS in pancreatic β-cell homeostasis. Blood CS levels in streptozotocin (STZ)- or high-fat diet-induced diabetic mice and patients with type 1 or 2 diabetes were determined by LC-MS/MS. The impact of CS on β-cell mass and insulin secretion was investigated in isolated mouse islets and the β-cell line INS-1 and in STZ-induced diabetic mice. The molecular mechanism of CS was explored by viability assay, EdU incorporation analysis, flow cytometry, intracellular Ca influx analysis, mitochondrial membrane potential and cellular ROS assays, and metabolism assay kits. Plasma CS levels in mice and humans were significantly elevated under diabetic conditions. CS attenuated diabetes in a low-dose STZ-induced mouse model. Mechanistically, CS promoted β-cell proliferation and protected β-cells against apoptosis under stressful conditions, which in turn preserved β-cell mass. In addition, CS supported glucose transporter-2 (GLUT2) expression and mitochondrial integrity, which then resulted in a less reactive oxygen species (ROS) generation and an increase in ATP production, thereby enabling insulin secretion machinery in the islets to function adequately. This study revealed a novel dual role of CS in integrating β-cell survival and cell function, suggesting that CS might offer a physiologic approach to preserve β-cells and protect against the development of diabetes mellitus.