Topic: Sphingolipid-mediated Signaling and Chronic Glucocorticoid Induced Glucose Homeostasis Disorders
Speaker：Jen-Chywan Wang (Nutritional Science and Toxicology University of California, Berkeley)
Time: November 16, 2023 1:30-3:00 pm
Venue: 醫學院第四講堂
Abstract：
Chronic and/or excess glucocorticoid (GC) exposure, such as prolonged stress and long-term GC therapy, causes metabolic disorders including hyperglycemia and insulin resistance. Intracellular GC receptor (GR) has been shown to directly stimulate the transcription of gluconeogenic genes, such as Pck1 and G6pc, to promote gluconeogenesis. However, chronic GC exposure induces additional mechanisms to further enhance hepatic gluconeogenesis and insulin resistance. We found that chronic GC exposure increases hepatic ceramides and sphingosine-1-phosphate (S1P) levels. Ceramides activate protein phosphatase 2A (PP2A) and protein kinase ζ (PKCζ). Reducing ceramide production and the activities of PP2A and PKCζ improves GC-induced insulin resistance. Intracellular S1P can be exported to the extracellular surface and binds to membrane S1P receptors (S1PRs) to exert its actions. We found that reducing the expression of hepatic S1P receptor 1, 2, and 3 (S1PR1-3) modulated glucocorticoid-regulated glucose homeostasis. Especially, hepatic S1PR2 knockdown attenuated chronic glucocorticoid-induced glucose intolerance, hepatic gluconeogenesis, gluconeogenic gene expression, GR recruitment to the glucocorticoid response elements (GREs) of gluconeogenic genes. Hepatic S1PR2 knockdown also enhanced glucocorticoid suppression of RAR-related orphan receptor gamma (RORγ ) expression. Hepatic RORγ overexpression in hepatic S1PR2 knockdown mice restored glucocorticoid-induced glucose intolerance, gluconeogenic gene expression, and GR recruitment to their GREs. Conversely, RORγ antagonist and the reduction of hepatic RORγ expression attenuated such glucocorticoid effects. Thus, chronic glucocorticoid exposure induces a S1PR2-RORγ axis to cooperate with GR to enhance hepatic gluconeogenesis. Overall, chronic GC exposure induce hepatic ceramide- and S1P-mediated signaling to enhance hyperglycemia and insulin resistance. Targeting these pathways is a potential approach to reduce GC therapy-induced glucose side effects.