Abstract
Rational: 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. Materials and Methods: 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 vitro in isolated mouse islets and the β-cell line INS-1 and in vivo in STZ-induced diabetic mice. The molecular mechanism of CS was explored by viability assay, EdU incorporation analysis, flow cytometry, intracellular Ca2+ influx analysis, mitochondrial membrane potential and cellular ROS assays, and metabolism assay kits. Results: 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. Conclusion: 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.
Highlights
Type 2 diabetes (T2D) is thought of as a progressive disease characterized by a gradual deterioration of pancreatic β-cell function and a reduction in β-cell mass, which occurs very early in the course of the disease (Chen et al, 2017; Esser et al, 2020)
Multiple low doses of STZ induce a mild impairment of insulin secretion that is more similar to the later stages of T2DM (Srinivasan et al, 2005)
The high-fat diet (HFD)-induced obese mouse is generally accepted as a T2DM model (Heydemann 2016) displaying hyperglycemia and a significantly higher body weight (Supplementary Figures S1G,H), and the plasma cholesterol sulfate (CS) level was detected to be remarkably higher than that in the lean mice (3.15 ± 0.37 μg/ml vs. 1.19 ± 0.10 μg/ml, p < 0.001) (Figure 1B)
Summary
Type 2 diabetes (T2D) is thought of as a progressive disease characterized by a gradual deterioration of pancreatic β-cell function and a reduction in β-cell mass, which occurs very early in the course of the disease (Chen et al, 2017; Esser et al, 2020). Recent evidence demonstrates that CS regulates glucose metabolism and energy homeostasis, directly, by inhibiting gluconeogenesis via the suppression of hepatocyte nuclear factor 4α (HNF4α) (Shi et al, 2014) and, indirectly, acts as a putative natural agonist of nuclear receptor retinoic acid-related orphan receptor α (RORα) (Kallen et al, 2004). The latter has been reported to be involved in the control of blood glucose levels and the occurrence of diabetes through the regulation of gluconeogenesis (Madsen et al, 2016; Zhang Xueping et al, 2018), lipogenesis (Kim et al, 2017), insulin production (Kuang et al, 2014) and insulin sensitivity (Liu et al, 2017a). The physiological function of CS in β-cells has not been defined
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