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Liver X Receptor Agonist T0901317 Inhibition of Glucocorticoid Receptor Expression in Hepatocytes May Contribute to the Amelioration of Diabetic Syndrome in db/db Mice

Division of Endocrinology (Y.L., Y.W., N.N., A.A., T.C.F.), Charles R. Drew University of Medicine and Sciences, University of California, Los Angeles, School of Medicine, Los Angeles, California 90059; Department of Pediatrics (C.Y.), First Hospital, JiLin University, ChangChun130021, China; Department of Pediatrics (Y.N.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan; and Department of Pharmaceutical Sciences (K.L.), College of Pharmacy, Western University of Health Sciences, Pomona, California 91766

Address all correspondence and requests for reprints to: Yanjun Liu, M.D., Ph.D., Division of Endocrinology, Metabolism, and Molecular Medicine. Charles R. Drew University of Medicine and Sciences, University of California, Los Angeles, School of Medicine, 1731 East 120th Street, Los Angeles, California 90059. E-mail: dryanjunliu{at}hotmail.com.

The glucocorticoid receptor (GR) is a crucial target gene for glucocorticoid-induced insulin resistance and hepatic gluconeogenesis linked to the development of type 2 diabetes. The liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of the metabolic gene linked to carbohydrate homeostasis. To assess the tissue-specific interaction of LXR with GR in the development of type 2 diabetes, we examined the possible effect of LXR agonist T0901317 on GR gene expression in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). Chronic ligand activation of LXR by a synthetic LXR T0901317 markedly decreased the expression of both GR mRNA and its protein in liver and improved the phenotype of type 2 diabetes in obese db/db mice. Suppression of hepatic GR expression was correlated with reduced levels of glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase mRNA and 11ß-hydroxysteroid dehydrogenase type 1-mediated synthesis of active corticosterone from inactive 11-dehydrocorticosterone in liver. Treatment of db/db mouse primary hepatocytes with T0901317 resulted in dramatic suppression of GR mRNA and required ongoing protein synthesis. Addition of T0901317 to primary hepatocytes also suppressed the expression of both 11ß-hydroxysteroid dehydrogenase type 1 and phosphoenolpyruvate carboxykinase. These findings suggest that some of antidiabetic actions of LXR agonist T0901317 may be mediated, at least in part, through the suppression of hepatic GR gene expression.

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