American Diabetes Association
Browse
1/1
3 files

Chronic Glucocorticoid Exposure Induced a S1PR2-RORg Axis to Enhance Hepatic Gluconeogenesis in Male Mice

figure
posted on 2023-08-08, 20:32 authored by Rebecca A. Lee, Maggie Chang, Ariel Tsay, Yeong Rim Lee, Danielle Li, Nicholas Yiv, Sharon Tian, Michelle Zhao, Richard M. O’Brien, Jen-Chywan Wang

It is well-established that chronic glucocorticoid exposure causes hyperglycemia. While glucocorticoid receptor (GR) stimulates hepatic gluconeogenic gene transcription, additional mechanisms are activated by chronic glucocorticoid exposure to enhance gluconeogenesis. We found that chronic glucocorticoid treatment activated sphingosine-1-phosphate (S1P)-mediated signaling. Hepatic knockdown of hepatic S1P receptor 1 (S1PR1) had no effect on chronic glucocorticoid-induced glucose intolerance but elevated fasting plasma insulin levels. In contrast, hepatic S1PR3 knockdown exacerbated chronic glucocorticoid-induced glucose intolerance without affecting fasting plasma insulin levels. Finally, hepatic S1PR2 knockdown attenuated chronic glucocorticoid-induced glucose intolerance and reduced fasting plasma insulin levels. Here we focused on dissecting the role of S1PR2 signaling in chronic glucocorticoid response on glucose homeostasis. We found that chronic glucocorticoid-induced hepatic gluconeogenesis, gluconeogenic gene expression, and GR recruitment to the glucocorticoid response elements (GREs) of gluconeogenic genes were all reduced in hepatic S1PR2 knockdown male mice. Hepatic S1PR2 knockdown also enhanced glucocorticoid suppression of RAR-related orphan receptor gamma (RORg) expression. Hepatic RORg overexpression in hepatic S1PR2 knockdown mice restored glucocorticoid-induced glucose intolerance, gluconeogenic gene expression, and GR recruitment to their GREs. Conversely, RORg antagonist and the reduction of hepatic RORg expression attenuated such glucocorticoid effects. Thus, chronic glucocorticoid exposure induces a S1PR2-RORg axis to cooperate with GR to enhance hepatic gluconeogenesis. Overall, this work provides novel mechanisms of and pharmaceutical targets against steroid-induced hyperglycemia.

Funding

This work was supported by the NIDDK R01 DK113019, DK124866 and DK131194. JCW is a member of the UCSF Liver Center (NIH P30 DK026743). Work in the laboratory of O’Brien is supported by DK132259. Model design: BioRender.

History

Usage metrics

    Diabetes

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC