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Natural sciences
- Other biological sciences
- Other natural sciences
Glucocorticoids are steroidal hormones that are valuable immune suppressors in inflammation. However, chronic treatment with glucocorticoids makes blood sugar levels go up and disturbs fat metabolism in the body. A reduction in adverse effects related to glucose and lipid regulation would be highly desirable in clinical applications. Our former studies show that peroxisome-proliferator activated receptor alpha (PPARalpha) activation, a fatty acid sensor, can block the glucocorticoidinduced diabetogenic effect. We recently discovered an underlying mechanism on how this combination treatment additionally influences genes that control lipid metabolism in liver cells. A nutrient-sensing kinase is found back in the chromatin of genes that are co-controlled by both receptors, especially in a fasting state. In cell culture, a combination of glucocorticoids and PPARalpha agonists can block inflammatory gene expression, better than steroids alone. Here, we propose to translate cell culture data to relevant animal models. We hypothesize that the nature/duration of the inflammatory insult and/or nutritional state of the cells may play a role in how efficient these nuclear receptors combat inflammation. We will investigate gene regulation mechanisms to find out if and how the nutritional state or the activity of a nutrient-sensing kinase may bring added therapeutic benefit when combining glucocorticoid receptor and PPAR receptor agonists to fight particular inflammatory states.