Editors' ChoiceImmune Disorders

Therapeutic Targeting for the Long Term

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Science Translational Medicine  15 Dec 2010:
Vol. 2, Issue 62, pp. 62ec193
DOI: 10.1126/scitranslmed.3002012

Although widely used as therapeutic agents for inflammatory and autoimmune disorders as well as post–organ transplant management, glucocorticoids (GCs)—catabolic steroids that raise blood glucose—are far from perfect drugs. When taken in large amounts for prolonged periods of time, GCs can have profound side effects, including diabetes, hypertension, osteoporosis, and muscle wasting. GCs are known to interact directly with the GC receptor (GR), a transcriptional regulatory protein, to exert their biological effects largely through the regulation of gene expression. However, the whole GC story may not be as simple as the GC–GR interaction. Rather, liver X receptors (LXRs)—transcription factors that are known primarily for their role in cholesterol homeostasis—may also be important players in the steroid story. In elegant experiments using wild-type (WT) mice and mice in which LXR was knocked out (LXR knockout mice; Lxrα–/–, Lxrβ–/–, and Lxrα/β–/–), Patel et al. now reveal a functional requirement for LXRs in the manifestation of adverse metabolic effects of exogenous GC administration. Specifically, these investigators demonstrated that LXRβ is required for the development of GC-induced hyperglycemia and hepatic steatosis.

In their study, Patel et al. exposed the WT and LXR knockout mice to dexamethasone—a GC that is commonly used in clinical practice—and showed that mice lacking LXRβ (but not LXRα) were resistant to GC-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to GC-mediated anti-inflammatory effects and repression of the immune system. They also revealed that LXRβ was required for GC-induced recruitment of the GR to the promoter of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK).

This study thus reveals the importance of the unexpected crosstalk between the GC receptor and LXRs, especially LXRβ. Specifically, it highlights the importance of LXRβ in the metabolic—but not anti-inflammatory—effects of prolonged systemic steroid administration. Given that many patients are subjected to high-dose GC therapy for long periods of time for allergic or autoimmune conditions, or after organ transplantation, this study suggests that a selective GC agonist may be developed to escape activation of LXRβ. Such an approach may avoid the adverse metabolic consequences of traditional GC therapy, while at the same time providing the important and desired anti-inflammatory immunosuppressive effects.

R. Patel et al., LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J. Clin. Invest. 1 December 2010 (10.1172/JCI41681). [Abstract]

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