S1PR2 Signaling in Chronic Glucocorticoid Exposure-Induced Metabolic Disorders
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ABSTRACT:
PROVIDER: PRJNA633023 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11794591.fastq.gz | Fastqsanger.gz | |||
| SRR11794592.fastq.gz | Fastqsanger.gz | |||
| SRR11794593.fastq.gz | Fastqsanger.gz | |||
| SRR11794594.fastq.gz | Fastqsanger.gz | |||
| SRR11794595.fastq.gz | Fastqsanger.gz |
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Project description:Glucocorticoids play a key role in metabolic adaptation during stress, such as fasting and starvation. Excess and/or chronic glucocorticoid exposure, however, cause metabolic disorders that include insulin resistance dyslipidemia and hepatic steatosis. We previously showed that chronic glucocorticoid treatment elevates hepatic production of ceramides and sphingosine-1-phosphate (S1P). Ceramides are converted to sphingosine that is further converted to S1P. We showed that ceramide-initiated signaling in turn inhibits insulin signaling and increases lipogenic program in hepatocytes. However, the role of S1P, a signaling molecule that modulates physiological responses through membrane S1P receptors (S1PRs), in glucocorticoid actions is unclear. Here we found that inhibiting S1PR2 activity, but not S1PR1 and S1PR3, resulted in improved glucocorticoid-induced insulin resistance. Similarly, reducing hepatic S1PR2 expression showed similar results. Interestingly, reducing S1PR2 expression did not affect the ability of glucocorticoids to modify insulin signaling. Instead, glucocorticoids enhanced gluconeogenesis was reduced. Moreover, glucocorticoid-induced dyslipidemia and fatty liver was also compromised in mice with reduced hepatic S1PR2 expression. Indeed, RNA sequencing analysis showed that lipogenic, gluconeogenic and glycolytic genes are significantly lower in glucocorticoid-treated hepatic S1PR2 knockdown mice than those of glucocorticoid-treated hepatic scramble small hairpin RNA (shRNA) expressing mice (Control). Overall, our studies highlight the importance role of S1PR2 signaling in the mediating glucocorticoid regulation on gluconeogenesis and hepatic lipid homeostasis.
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